- freely available
Int. J. Mol. Sci. 2013, 14(10), 19416-19433; doi:10.3390/ijms141019416
Abstract: Chemical carcinogens are substances which induce malignant tumours, increase their incidence or decrease the time taken for tumour formation. Often, exposure to chemical carcinogens results in tissue specific patterns of tumorigenicity. The very same anatomical, biochemical and physiological specialisations which permit the kidney to perform its vital roles in maintaining tissue homeostasis may in fact increase the risk of carcinogen exposure and contribute to the organ specific carcinogenicity observed with numerous kidney carcinogens. This review will address the numerous mechanisms which play a role in the concentration, bioactivation, and uptake of substances from both the urine and blood which significantly increase the risk of cancer in the kidney.
1. Cancer of the Kidney
The incidence of renal cancer in the European Union per head of population is approximately 15.8 and 7.1 per 100,000 for males and females respectively . The incidence of renal cancers has declined slightly over the past decade in both the European Union and the United States following a decade-on-decade increase since 1950 . The term renal cancer is an umbrella term describing a heterogeneous group of renal diseases. Multiple forms of renal cancer have been identified and they are further classified based on their location, tissue of origin and physiological properties. Renal cell carcinoma (RCC) is the most common form of renal cancer in humans  and is the form that will be focused on in this review
2. Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most prevalent neoplastic renal disease, accounting for 90%–95% of all reported renal cancers [3,4]. Clear cell renal carcinoma (ccRCC) arises from the epithelium of the proximal tubule and being the most common form of RCC, is also the most widespread form of renal cancer. ccRCC is named for the clear appearance of the cytosol when stained using common histological staining techniques due to the increased lipid accumulation.
Loss of function of the protein Von Hippel-Lindau (VHL) has been implicated in the majority of ccRCC cases. VHL in conjunction with elongin B, elongin C and cullin [5,6], form an E3 ubiquitin-ligase complex which plays a role in the ubiquitination, and subsequent proteolysis of hypoxia inducible factor-1α (HIF-1α) under normoxic conditions . Hypoxia or a loss of function mutation in VHL allows accumulation and nuclear translocation of HIF-1α. Once in the nucleus, HIF-1α may homodimerise, or heterodimerise with HIF-1β whereby it functions as a co-transcription factor increasing the expression of numerous genes known to play a role in cancer including vascular endothelial growth factor, platelet derived growth factor, and the Glut-1 glucose transporter [8,9]. It is interesting to note that although the VHL mutation is observed in the majority of familial ccRCC cases, less than 4% of ccRCC cases are familial in nature, with the vast majority being accounted for by sporadic carcinogenesis (reviewed in [10,11]), yet between 60% and 70% of these sporadic cases also exhibit loss of VHL function either through point mutation, or promoter hypermethylation indicating the importance of VHL in ccRCC [12,13].
Aberrant HIF signalling not only promotes tumourigenesis through sustained mitogenic signalling and encouragement of vascularisation, but also disrupts the metabolic status of cancerous cells. As mentioned previously, Glut-1 expression is Hormone Response Element (HRE) dependent, and is commonly found to be upregulated in clear cell renal carcinoma . Increased expression of Glut-1 increases glucose uptake into the cell, which facilitates the increased glucose consumption that cancerous cells are known to exhibit. Also under the transcriptional regulation of HIF are both lactate dehydrogenase (LDH) and the monocarboxylate transporter 4 (MCT4) [14,15]. Lactate dehydrogenase catalyses the conversion of pyruvate to lactate and MCT4 transports lactate out of the cell. Production of lactate by cancerous cells, and its subsequent transport to the extracellular environment helps to acidify the tumour microenvironment. This local acidification helps to further promote tumourigenesis through increased Extrcellular Matrix (ECM) degradation. It has previously been shown that in response to a decrease in pH, there is an increase in excretion of lysosomal protease cathepsin B, which helps to degrade the ECM, into the extracellular space . In addition to this, it has been shown that membrane type 2 matrix metalloproteinase (MT2-MMP) is under the transcriptional regulation of HIF. Given that the ECM functions as a barrier to keep cancerous cells in situ, its degradation contributes towards the likelihood of a cancer spreading to areas beyond the initial lesion. In addition to this, numerous growth factors are embedded within the ECM (reviewed by ). Degradation of the ECM is believed to play a crucial role in tumour progression, as proteolytic cleavage of the ECM releases these latent growth factors .
3. Chemical Carcinogenicity
Chemical carcinogens are, by definition, substances which when ingested, inhaled, applied to the skin or which in other ways acquire access to tissues of the body, induce malignant tumours, increase their incidence or decrease the time taken for tumour formation  (Table 1). The very same anatomical, biochemical and physiological specialisations which permit the kidney to perform its vital roles in homeostasis may increase the risk of carcinogen exposure to the components of the nephron and its ancillary structures.
4. Susceptibility of the Kidneys to Chemical Carcinogenesis
4.1. Concentrating Effect
The kidneys receive approximately 25% of cardiac output and filter the plasma the equivalent volume of the entire extracellular fluid several times over each day. As a result the risk of exposure to carcinogens is disproportionately high for the epithelium of the nephron when compared to epithelial tissue found elsewhere in the body. In addition to this, one of the primary functions of the kidney is the creation of concentrated urine. Removal of waste products from systemic circulation and excretion into the urine means that as water and solutes are reabsorbed from the urine the concentration of waste products, including carcinogens increases. As such, the epithelium of the nephron would appear to be at a significantly greater risk of from blood borne carcinogens than other epithelial tissues.
4.2. Xenobiotic Metabolizing Capability—Bio-Activation of Pro-Carcinogens
The kidney is a biochemically active organ and contributes significantly to metabolism of xenobiotics. Lipophilic substances, for example, are not removed efficiently by the kidney and as such, addition of a polar group allows for the efficient clearance of these substances. One such class of enzymes which perform this function, also known as phase I metabolism, are the cytochrome p450 mono-oxygenases (also known as CYPs). While the majority of cytochrome p450 enzymatic activity occurs in the liver, CYPs are also expressed in other tissues including the kidney  and CYP activity in the kidney also contributes to the oxidative metabolism and subsequent removal of many classes of xenobiotics from systemic circulation.
While the CYP super family usually contributes to the detoxification of xenobiotics, there are instances whereby oxidation results in the creation of a toxic metabolite. The enzymatic activity of several CYP enzymes has been shown to result in the bio-activation of non-carcinogenic pro-carcinogens to their carcinogenic form. CYP1A1 for example, which is known to play a role in the bioactivation of benzo[a]pyrene to the carcinogenic benzo[a]pyrene-diol-epoxide-I-1 , is expressed at low levels in the kidney, however it can be induced by hydrocarbon compounds, and inter-individual differences in expression are believed to be a factor in determining the susceptibility of an individual to benzo[a]pyrene induced carcinogenesis . NAD(P)H dehydrogenase (quinone) 1 (NQO1) is another phase I metabolising enzyme with reductive capacity. The IARC Group 1 carcinogen aristolochic acid undergoes nitroreduction to the pro-carcinogen intermediate aristolochic acid-I (AA-I) through the actions of NQO1 
Phase II reactions generally involve conjugation of the phase I metabolite with glucuronic acid glutathione, amino acids or sulfonates. While conjugation usually results in the amelioration of the toxicity of a particular metabolite, there are several known instances whereby conjugation results in the bioactivation of pro-carcinogens to their carcinogenic metabolites. It has been shown that overexpression of sulfotransferase 1 (SULT1), which mediates the conjugation of a sulphate group, increases aristolochic acid DNA adduct formation . Certain pro-carcinogens require a concerted effort between phase I and phase II metabolising enzymes to result in bioactivation. 2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC), for example requires both CYP1A2 and SULT1A1 expression, but does not induce an increased mutation rate when either CYP1A2 or SULT1A1 are replaced with other CYP or SULT forms.
4.3. The Organic Ion Transport Systems
While filtration by the glomerulus is the primary mechanism for removal of xenobiotics and waste products from the blood, these compounds can also be excreted directly from the blood into the lumen of the nephron via transcellular transport. As one of the functions of the nephron is removal of xenobiotics from systemic circulation, the epithelium of the nephron is endowed with specific transport mechanisms to allow the transport of polar xenobiotics across the monolayer in such a fashion (reviewed by [25,26]).
As this excretion pathway involves transcellular transport, anionic and cationic compounds including carcinogens, which would otherwise not cross the plasma membrane, are granted access to the cytosol and depending on the mechanism of action of the carcinogen in question may interact with the genome or interfere with other cellular processes (Figure 1).
Several carcinogens are known to be handled by the organic anion transport (OAT) family of transport proteins. Several organic anion transporters, including OAT1, OAT2 and OAT3 have been shown to have an affinity for aristolochic acid (AA), and result in a subsequent increase in uptake of the pro-carcinogen AA-I in toxicologically relevant concentrations in mouse models . The organic cation transport (OCT) family has also been implicated in facilitating the uptake of potential carcinogens into the cells of the nephron. Ethidium, a mutagenic vital dye, is membrane impermeable and must be transported into the cell to gain access to the DNA. OCT1, OCT2 and OCT3 have all been shown to mediate the transport of ethidium into the proximal tubular epithelial cells of rats expressing human OCT transporters .
5. Mechanisms of Chemical Carcinogenicity
Cancer is a broad term which covers a range of distinct pathologies from solid to haematological tumours which can arise in almost any organ or tissue in the body. Given that cancer describes such a large group of related disease types it is perhaps unsurprising that there are a large number of chemical carcinogens with numerous methods of action and selectivity for various tissue types. Classification of chemical carcinogens is complex, and depending on the region, may be classified in numerous different ways. These classification methods may be simplified however, as carcinogenic agents are often simply described as either genotoxic or non-genotoxic carcinogens (Figure 2).
Polar substances cannot readily cross the plasma membrane. The transport of the polar waste products across the epithelial monolayer of the proximal tubule, is facilitated by a family of solute carrier proteins, including members of the organic anion transport (OAT) and organic cation transport (OCT) family. Polar molecules, which may not gain access to the cytosol otherwise, may do so via the actions OCT/OAT system. Carcinogens may then either directly interact with and damage DNA, in the case of genotoxic carcinogens, or may act through secondary mechanisms such as steroid hormone receptors (SHR) or reactive oxygen species (ROS) generation to promote carcinogenesis in the case of non-genotoxic carcinogens.
5.1. Genotoxic Carcinogenicity
Genotoxic carcinogens are agents which covalently bind, or in some other way physically interact with the DNA to induce adducts . As such, genotoxic carcinogens may be regarded as initiators of carcinogenesis, capable of producing the genetic damage needed to acquire the mutations that initiate cancerous change. The majority of genotoxic carcinogens require metabolic activation. As such, in their native form, these substances are often non-carcinogenic. However, phase I metabolism results in reduction of these substances with the subsequent addition of electrophilic functional groups promoting interaction with the DNA double helix (reviewed by ). Covalent binding of these genotoxic metabolites leads to adduct formation, which can induce mutations in several distinct ways. Bulky adducts such as those formed by benzo[a]pyrene for example, may be large enough to hinder DNA polymerases, and therefore introduce mutations through the inclusion of incorrect nucleotides . Numerous alkylating agents result in the formation of the N7-alkylguanine adduct which weakens the bond connecting the base of a nucleotide to the deoxyribose, thereby increasing the likelihood of an apyrimidinic or apurinic nucleotide (also known as an abasic inclusion) into the genome .
5.2. Non-Genotoxic Carcinogenicity
Non-genotoxic carcinogens are a more diverse group of chemicals in terms of their mechanisms of action and chemical properties. As opposed to genotoxic carcinogens which are capable of altering the genetic sequence and directly initiating carcinogenic mutations, non-genotoxic carcinogens may be regarded as tumour promoting agents, that is, they encourage the clonal expansion of cells which have already acquired carcinogenic mutations Non-genotoxic carcinogens do not interact directly with the DNA to promote tumour progression; however there are many physiological processes which control cell growth and division which are potential targets for these agents. Included among these are receptor and non-receptor mediated endocrine modulation [32,33], cytotoxicity and immunosuppression [34,35] and interference with gap junction intercellular communication . Chloroform (Table 2d) is an example of a non genotoxic carcinogen as neither chloroform nor its metabolites are capable of interacting directly with DNA. It is able to induce low to moderate cases of renal tubule tumours in male rats, as well as damage that is localised to the proximal convoluted tubule cells in mice . It is able to induce a transient increase the number of proliferating cells . Gap junctions are associated with the intracellular homeostasis of growth regulatory signals and the disruption of this intracellular communication by the loss of connexin plaques (Cx) has been shown to be implicated in the cancer process. Connexins are proteins that form gap junctions. It was observed in some studies that chloroform caused a dose dependent decrease in Cx plaques containing Cx32 in proximal tubules in vivo . However, the diversity of possible mechanisms of action of non-genotoxic carcinogens has made the identification of this class of compounds through standard carcinogen screening systems difficult. Identifying these carcinogens by classical methods becomes even more complex when it is taken into account that many of the aforementioned pathways are tissue and species specific, and that any one carcinogen may cause dysregulation of multiple pathways.
6. Renal Carcinogens
Ochratoxin-A (OTA) is a secondary metabolite produced by several species of the Aspergillus and Penicillium genera of moulds [39–41]. OTA contamination has been described in a wide range of foods and beverages including meat, grain, cereals, coffee, grapes, wine and beer produced globally [42–45]. OTA is a known nephrotoxin in both man and animal. In addition to these nephrotoxic effects, OTA is classed as one of the most potent rodent renal carcinogens [46,47]. Moreover, neoplastic lesions induced by OTA have been shown to be highly metastatic in vivo . While no definitive proof exists that OTA exposure results in tumour formation in humans , there is sufficient evidence based on rodent testing to suggest that OTA is a possible human carcinogen and is therefore classified as a class IIb carcinogen under the International Agency for Research on Cancer (IARC) classification criteria.
Structurally, OTA is composed of a chlorinated dihydroisocoumarin bound to a phenylalanine moiety (Table 2a). As a result, OTA has been shown to compete with phenylalanine and inhibit enzymes for which phenylalanine is a substrate . This is further supported by the fact that supplementation with phenylalanine has been shown to prevent OTA toxicity in an in vivo model . Glomerular filtration of ochratoxin A is negligible as the majority is bound to plasma proteins , and as such, the major route of cellular entry is via the organic anion transport system, highlighting the renal specificity associated with OTA induced toxicity. In vivo and in vitro studies have shown that inhibition of organic anion transport with probenecid prevents OTA renal clearance [53,54], indicating that excretion of OTA occurs via this transcellular organic anion transport system.
However the mechanisms by which OTA induces neoplastic lesions in the proximal tubule are less clearly defined. Much work has been carried out in efforts to determine whether OTA should be classified as a genotoxic or non-genotoxic carcinogen. Given the frequency with which OTA is found as a contaminant in food and drink, reclassification of OTA as a genotoxic carcinogen would have serious implications for the food and drink industry as a 10-fold reduced human risk differential may be applied when evaluating a non-genotoxic carcinogen versus a carcinogen with a confirmed genotoxic mechanism of action . To elucidate the mechanisms by which OTA induces genomic instability many studies have focussed on proving the existence of OTA-DNA adducts as an indicator of direct genotoxicity . 32P-postlabelling experiments  in in vitro models have shown OTA/DNA interaction resulting in an A-2′-deoxyguanosine adduct (dGuoOTA). 1H-NMR studies have also shown the formation of dGuoOTA in cell-free systems . The origin of such adducts has been the subject of much debate. Radiolabelling experiments thus far have failed to demonstrate the existence of direct interaction of OTA, or OTA metabolites, with genomic DNA [57–59], with several studies concluding that the proposed DNA adduct is likely a result of cytotoxicity, as opposed to genotoxicity. It has been shown that OTA exposure results in an increase in reactive oxygen species (ROS) accumulation in proximal tubular epithelial cells . Abasic DNA lesions are lesions wherein hydrolysis results in the loss of a base. Such lesions result in the loss of genetic information and are therefore potentially cancer causing. Treatment with OTA has been shown to result in abasic DNA lesions in vitro and in vivo . Oxidative stress resulting from the depletion of glutathione  and superoxide dismutase (SOD)  as well as increased NO  has been implicated in the generation of these abasic lesions.
6.2. Potassium Bromate
Potassium bromate (KBrO3) is a salt which is used as an oxidising agent. Its oxidising properties have led to it being used as a maturing agent in the processing of flour. While used in the USA as a flour maturation agent since 1914, KBrO3 has been banned in the E.U., Canada, Sri Lanka, China, Brazil, Nigeria and Peru as a food additive. While in the E.U. at least, KBrO3 is no longer a legal food additive, exposure through contaminated drinking water is still possible. The ozonation process used to sterilise drinking water, in the presence of bromine, may give rise to the formation of KBrO3. KBrO3 has been shown to be nephrotoxic to humans and laboratory animals, and is currently classed as an IARC class IIb carcinogen .
Potassium bromate is composed of a bromic acid moiety bound to a potassium salt (Table 2b). While once commonly used as a food additive, it has been demonstrated that KBrO3 is both toxic, and potentially carcinogenic in humans. KBrO3 toxicity may arise as a result of the oxidative properties of the molecule. Oxidative stress has been shown to arise in numerous model systems following KBrO3 exposure and is believed to be the key mechanism of toxicity. It has been demonstrated in vivo that concentrations of malondialdehyde, a marker of lipid peroxidation and oxidative stress which are increased following KBrO3 exposure, are reduced when co-treated with the anti-oxidant melatonin . Numerous other studies have demonstrated attenuation of KBrO3 toxicity in the presence of antioxidants indicating that oxidative stress is a probable causal factor in KBrO3 induced toxicity [67,68].
Oxidative stress is also believed to be the causal factor in KBrO3 induced carcinogenesis. KBrO3 exposure has been shown to result in the formation of the oxidative DNA adduct 8-hydroxyguanine (8-OHdG) [69,70]. Administration of numerous antioxidants, including resveratrol and vitamin E, have been shown to diminish the formation of 8-OHdG, indicating that the mutagenic activity of may be at least in part, dependent on the production of reactive oxygen species . Indeed, in another in vivo study the antioxidant sodium ascorbic acid was shown to significantly decrease 8-OHdG adduct formation in the kidneys of both male and female mice .
6.3. Aristolochic Acid
Aristolochic acid (AA) is a naturally occurring alkaloid compound found in extracts of the Aristolochia species of plants which can sometimes be found in alternative medicines, mainly due to errors in plant collecting . Exposure to Aristolochic acid can be unintentional or else the person can knowingly consume it in some herbal medicines that were popular in some areas of the world, in particular China, despite wide scale evidence of the damage it inflicts. AA has been singled out as the cause of Chinese herbal nephropathy (CHN) which has since become known as aristolochic acid nephropathy (AAN). AAN is a rapidly progressing fibrotic disease of the kidney, and it has been discovered that AAN patients are at a significantly higher risk of developing renal cancer . Indeed AA has since been classified as an IARC Group 1 carcinogen , and is believed to be amongst the most potent known human carcinogens.
Aristolochic acid is composed of a mixture of related nitrophenanthrene compounds (Table 2c). The most prevalent however are 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid, which is commonly referred to as AAI and 6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid which is referred to as AAII. Both AAI and AAII are metabolised primarily by CYP1A, CYP1A2  to DNA reactive species. AA-DNA adducts derived from both AAI and AAII metabolites have been identified [76,77], however the most persistent adduct in the kidney, 7-(deoxyadenosin-N6-yl) aristolactam I, known as (dA-AAI) is a known mutagenic lesion. This mutagenic lesion has been shown to give rise to transversion of adenine to thymine. Indeed several studies have shown that this transversion mutation has a particularly detrimental role in the progression of cancer. In samples from an AAN patient, the dA-AAI adduct was shown to induce mutation of AAG (lysine) to TAG (stop codon) in exon 5 of the p53 gene . Additionally, constitutive activation of H-ras has also been demonstrated in laboratory animals fed AA containing diets as a result of dA-AAI mediated A:T transversion mutations [79,80].
7. Screening for Chemical Carcinogens
Given the number of chemical substances that humans are exposed to each day, identifying those substances which are potential carcinogenic hazards is perhaps the most important step in the risk assessment process for chemical carcinogens. Current legislation is focused on the reduction in the volume of animal studies used for toxicological assessment (reference REACH) and as such, there is an increasing drive towards the implementation of in vitro models in the carcinogen screening. However, on the 1st of June, 2007, new European legislation called REACH (Registration, Evaluation and Authorisation of Chemical substances) came into force. The introduction of REACH however mandates the full carcinogenicity testing of some 100,000 chemical substances. Currently, the two year rodent bioassay is the gold standard for determining the carcinogenic potential of a given substance. The use of animal studies is based on the physiological similarity that exists across mammalian species and on the assumption that agents causing cancer in animals will have similar effects in humans [85,86]. Indeed virtually all known human carcinogens have been shown to cause cancer in animal tests. While the in vivo rodent bioassay is the accepted “gold-standard” approach to carcinogen screening as mentioned previously, there are numerous drawbacks associated with the use of a rodent model in the implementation of the REACH legislation. The most apparent is the scale of testing required under REACH. Estimates of the number of animals necessary to fully screen the compounds covered by REACH are as high as 45 million , however more conservative, and perhaps more realistic estimates place the number of required animals at 12 million . Regardless of the exact number of animals required, the implementation of such large scale in vivo screening program is clearly in contrast to the “Reduce, Refine and Replace” strategy advocated by the E.U. in terms of animal use.
8. Conclusions and Future Studies
The physiological functions performed by the epithelium of the proximal tubule, by their very nature, increase the risk of exposure of these cells to blood borne chemical carcinogens. The concentrating and metabolising mechanisms, which are required for the efficient removal of waste from the body, make this tissue a unique target for chemical carcinogenicity. As such, it is essential that the future of carcinogenicity testing include a renal specific component should the in vitro approach be adopted. Multiple E.U. projects have been implemented to develop novel, high throughput risk assessment platforms with this in mind. These projects include the EU funded ACuteTox [89,90], Predictomics  and carcinoGENOMICS , programs, which were implemented to assess the use of cell culture based organ-specific toxicity screening platforms, thereby reducing the animal burden involved in that aspect of REACH implementation. Alternative methods assessing the physiological impact of carcinogen exposure are currently being investigated in tandem [93,94], such as deciliation following carcinogen exposure , or colony formation using the cell transformation assay (CTA) [95,96]. The scale of these efforts highlights the gravity of the threat posed to the kidney by carcinogenic substances, and the seriousness with which these threats should be taken.
|Table 1. IARC carcinogen classification for compounds affecting the renal and urinary system: Several examples of chemical substances which are either known or suspected to induce cancers of the kidney and urinary system. IARC grouping: Class 1—known to cause cancer in humans, Class 2A—probably carcinogenic to humans, Class 2B—possibly carcinogenic to humans, Class 3—not found to be carcinogenic to humans.|
|Site||Compound||Possible source of exposure||IARC Classification|
|Kidney||2-Nitrofluorene||By-product of combustion||2B|
|Aristolochic Acid||Use of aristolochia in herbal medicine||1|
|Arsenic||Contamination of drinking water||2A|
|Benzo[a]pyrene||Motor vehicle exhaust fumes||2A|
|Bromodichloromethane||Chlorination of drinking water||2B|
|Cadmium||Cigarette smoking, industrial activity||2A|
|Ochratoxin A||Fungal contamination||2B|
|Potassium Bromate||By-product of water bromination||2B|
|Renal pelvis and ureter||Aristolochic acid||Aristolochia species||1|
|Phenacetin (and Phenacetin containing mixtures)||Non-steroidal anti-inflammatory medication||2A|
|Urinary bladder||2-Napthylamine||Cigarette smoking, industrial exposure||1|
|4-Aminobiphenyl||Cigarette smoking, industrial exposure||1|
|Arsenic||Contamination of drinking water||1|
|Benzidine||Benzidine based dyes||1|
|Chlornaphazine||Discontinued pharmaceutical agent||1|
|Table 2. Structure of Ochrotoxin A  (a); Potassium bromated  (b); Aristolochic Acid  (c) and Chloroform  (d).|
This work was funded by the EU 6th Framework grant “carcinoGENOMICS”, 7th Framework grant “SysKid” and the CEFIC Long-range Research Initiative.
Conflicts of Interest
The authors declare no conflict of interest.
- Ljungberg, B.; Campbell, S.C.; Choi, H.Y.; Jacqmin, D.; Lee, J.E.; Weikert, S.; Kiemeney, L.A. The epidemiology of renal cell carcinoma. Eur. Urol 2011, 60, 615–621.
- Levi, F.; Lucchini, F.; Negri, E.; La Vecchia, C. Declining mortality from kidney cancer in Europe. Ann. Oncol 2004, 15, 1130–1135.
- Ng, C.S.; Wood, C.G.; Silverman, P.M.; Tannir, N.M.; Tamboli, P.; Sandler, C.M. Renal cell carcinoma: Diagnosis, staging, and surveillance. AJR Am. J. Roentgenol 2008, 191, 1220–1232.
- Eble, J.N. Pathology and genetics of tumours of the urinary system and male genital organs. BJU Int 2004, 94, 675.
- Kibel, A.; Iliopoulos, O.; DeCaprio, J.A.; Kaelin, W.G., Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995, 269, 1444–1446.
- Pause, A.; Lee, S.; Worrell, R.A.; Chen, D.Y.T.; Burgess, W.H.; Linehan, W.M.; Klausner, R.D. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl. Acad. Sci. USA 1997, 94, 2156–2161.
- Maxwell, P.H.; Wiesener, M.S.; Chang, G.; Clifford, S.C.; Vaux, E.C.; Cockman, M.E.; Wykoff, C.C.; Pugh, C.W.; Maher, E.R.; Ratcliffe, P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399, 271–275.
- Wiesener, M.S.; Münchenhagen, P.M.; Berger, I.; Morgan, N.V.; Roigas, J.; Schwiertz, A.; Jürgensen, J.S.; Gruber, G.; Maxwell, P.H.; Löning, S.A.; et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res 2001, 61, 5215–5222.
- Krieg, M.; Haas, R.; Brauch, H.; Acker, T.; Flamme, I.; Plate, K.H. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 2000, 19, 5435–5443.
- Pavlovich, C.P.; Schmidt, L.S. Searching for the hereditary causes of renal-cell carcinoma. Nat. Rev. Cancer 2004, 4, 381–393.
- Zbar, B.; Klausner, R.; Linehan, W.M. Studying cancer families to identify kidney cancer genes. Annu. Rev. Med 2003, 54, 217–233.
- Giménez-Bachs, J.M.; Salinas-Sánchez, A.S.; Sánchez-Sánchez, F.; Lorenzo-Romero, J.G.; Donate-Moreno, M.J.; Pastor-Navarro, H.; Carrión-López, P.; Escribano-Martínez, J.; Virseda-Rodríguez, J.A. VHL protein alterations in sporadic renal cell carcinoma. Clin. Oncol 2007, 19, 784–789.
- Herman, J.G.; Latif, F.; Weng, Y.; Lerman, M.I.; Zbar, B.; Liu, S.; Samid, D.; Duan, D.S.; Gnarra, J.R.; Linehan, W.M. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl. Acad. Sci. USA 1994, 91, 9700–9704.
- Firth, J.D.; Ebert, B.L.; Ratcliffe, P.J. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J. Biol. Chem 1995, 270, 21021–21027.
- Ullah, M.S.; Davies, A.J.; Halestrap, A.P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem 2006, 281, 9030–9037.
- Rozhin, J.; Sameni, M.; Ziegler, G.; Sloane, B.F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res 1994, 54, 6517–6525.
- Taipale, J.; Keski-Oja, J. Growth factors in the extracellular matrix. FASEB J 1997, 11, 51–59.
- Dallas, S.L.; Rosser, J.L.; Mundy, G.R.; Bonewald, L.F. Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J. Biol. Chem 2002, 277, 21352–21360.
- European Commission Health and Consumer Directorate-General. Draft Report on Alternative (Non-animal) Methods for Cosmetics Testing: Current Status and Future Prospects—2010, Available online: http://ec.europa.eu/consumers/sectors/cosmetics/files/pdf/animal_testing/introduction_public_consultation_at_en.pdf (accessed on 25 April 2013).
- Choudhary, D.; Jansson, I.; Stoilov, I.; Sarfarazi, M.; Schenkman, J.B. Expression patterns of mouse and human CYP orthologs (families 1–4 during development and in different adult tissues. Arch. Biochem. Biophys 2005, 436, 50–61.
- Uppstad, H.; Øvrebø, S.; Haugen, A.; Mollerup, S. Importance of CYP1A1 and CYP1B1 in bioactivation of benzo[a]pyrene in human lung cell lines. Toxicol. Lett 2010, 192, 221–228.
- Plottner, S.; Plöttner, S.; Borza, A.; Wolf, A.; Bolt, H.M.; Kuhlmann, J.; Föllmann, W. Evaluation of time dependence and interindividual differences in benzo[a]pyrene-mediated CYP1A1 induction and genotoxicity in porcine urinary bladder cell cultures. J. Toxicol. Environ. Health Part A 2008, 71, 969–975.
- Chen, M.; Gong, L.; Qi, X.; Xing, G.; Luan, Y.; Wu, Y.; Xiao, Y.; Yao, J.; Li, Y.; Xue, X. Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction of aristolochic acid I and attenuates its nephrotoxicity. Toxicol. Sci 2011, 122, 288–296.
- Meinl, W.; Pabel, U.; Osterloh-Quiroz, M.; Hengstler, J.G.; Glatt, H. Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue. Int. J. Cancer 2006, 118, 1090–1097.
- Berkhin, E.B.; Humphreys, M.H. Regulation of renal tubular secretion of organic compounds. Kidney Int 2001, 59, 17–30.
- Launay-Vacher, V.; Izzedine, H.; Karie, S.; Hulot, J.S.; Baumelou, A.; Deray, G. Renal tubular drug transporters. Nephron. Physiol 2006, 103, 97–106.
- Dickman, K.G.; Sweet, D.H.; Bonala, R.; Ray, T.; Wu, A. Physiological and molecular characterization of aristolochic acid transport by the kidney. J. Pharmacol. Exp. Ther 2011, 338, 588–597.
- Lee, W.-K.; Reichold, M.; Edemir, B.; Ciarimboli, G.; Warth, R.; Koepsell, H.; Thévenod, F. Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am. J. Physiol. Renal Physiol 2009, 296, F1504–F1513.
- Williams, G.M. Mechanisms of chemical carcinogenesis and application to human cancer risk assessment. Toxicology 2001, 166, 3–10.
- Enoch, S.J.; Cronin, M.T.D. A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit. Rev. Toxicol 2010, 40, 728–748.
- Casarett, L.J.; Doull, J.; Klaassen, C.D. Casarett and Doull’s Toxicology: The Basic Science of Poisons; McGraw Hill Professional: New York, NY, USA, 2008.
- Pomorski, L.; Bartos, M.; Okruszek, A.; Matejkowska, M.; Tazbir, J.; Kuzdak, K. Carcinogenic effect of combined administration of 2,4-diaminoanisole sulfate, 4,4′-thiodianiline and N,N′-diethylthiourea in male Wistar rats. Neoplasma 2002, 49, 247–250.
- Aubé, M.; Larochelle, C.; Ayotte, P. 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) disrupts the estrogen-androgen balance regulating the growth of hormone-dependent breast cancer cells. Breast Cancer Res 2008, 10, R16.
- Van Kesteren, P.C.E.; Beems, R.B.; Luijten, M.; Robinson, J.; de Vries, A.; van Steeg, H. DNA repair-deficient Xpa/p53 knockout mice are sensitive to the non-genotoxic carcinogen cyclosporine A: Escape of initiated cells from immunosurveillance? Carcinogenesis 2009, 30, 538–543.
- Xu, J.; Walsha, S.B.; Verneya, Z.M.; Kopelovichc, L.; Elmetsa, C.A.; Athar, M. Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway. Biochem. Biophys. Res. Commun 2011, 408, 363–368.
- Sai, K.; Kangb, K.; Hirosec, A.; Hasegawac, R.; Troskod, J.E.; Inoue, T. Inhibition of apoptosis by pentachlorophenol in v-myc-transfected rat liver epithelial cells: Relation to down-regulation of gap junctional intercellular communication. Cancer Lett 2001, 173, 163–174.
- Mally, A.; Chipman, J.K. Non-genotoxic carcinogens: Early effects on gap junctions, cell proliferation and apoptosis in the rat. Toxicology 2002, 180, 233–248.
- Hard, G.C. Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent. Toxicol. Pathol 1998, 26, 104–112.
- Taniwaki, M.H.; Pitt, J.I.; Teixeira, A.A.; Iamanaka, B.T. The source of ochratoxin A in Brazilian coffee and its formation in relation to processing methods. Int. J. Food Microbiol 2003, 82, 173–179.
- Magnoli, C.; Violante, M.; Combina, M.; Palacio, G.; Dalcero, A. Mycoflora and ochratoxin-producing strains of Aspergillus section Nigri in wine grapes in Argentina. Lett. Appl. Microbiol 2003, 37, 179–184.
- Copetti, M.V.; Pereira, J.L.; Iamanaka, B.T.; Pitt, J.I.; Taniwaki, M.H. Ochratoxigenic fungi and ochratoxin A in cocoa during farm processing. Int. J. Food Microbiol 2010, 143, 67–70.
- Sørensen, L.M.; Mogensen, J.; Nielsen, K.F. Simultaneous determination of ochratoxin A, mycophenolic acid and fumonisin B(2) in meat products. Anal. Bioanal. Chem 2010, 398, 1535–1542.
- Juan, C.; Pena, A.; Lino, C.; Moltó, J.C.; Mañes, J. Levels of ochratoxin A in wheat and maize bread from the central zone of Portugal. Int. J. Food Microbiol 2008, 127, 284–289.
- Noonim, P.; Mahakarnchanakul, W.; Nielsen, K.F.; Frisvad, J.C.; Samson, R.A. Isolation, identification and toxigenic potential of ochratoxin A-producing Aspergillus species from coffee beans grown in two regions of Thailand. Int. J. Food Microbiol 2008, 128, 197–202.
- Martínez-Culebras, P.V.; Crespo-Semperea, A.; Sánchez-Hervása, M.; Elizaquivelb, P.; Aznarb, R.; Ramónb, D. Molecular characterization of the black Aspergillus isolates responsible for ochratoxin A contamination in grapes and wine in relation to taxonomy of Aspergillus section Nigri. Int. J. Food Microbiol 2009, 132, 33–41.
- Lock, E.A.; Hard, G.C. Chemically induced renal tubule tumors in the laboratory rat and mouse: Review of the NCI/NTP database and categorization of renal carcinogens based on mechanistic information. Crit. Rev. Toxicol 2004, 34, 211–299.
- NTP. Toxicology and Carcinogenesis Studies of Ochratoxin A (CAS No 303-47-9) in F344/N Rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser 1989, 358, 1–142.
- Boorman, G.A.; McDonald, M.R.; Imoto, S.; Persing, R. Renal lesions induced by ochratoxin A exposure in the F344 rat. Toxicol. Pathol 1992, 20, 236–245.
- IARC. International Agency for Research on Cancer (IARC)—Summaries & Evaluations Ochratoxin A (Group 2B), 2003. Available online: http://www.inchem.org/documents/iarc/vol56/13-ochra.html (accessed on 25 April 2013).
- Zanic-Grubisić, T.; Zrinski, R.; Čepelak, I.; Petrik, J.; Radić, B.; Pepeljnjak, S. Studies of ochratoxin A-induced inhibition of phenylalanine hydroxylase and its reversal by phenylalanine. Toxicol. Appl. Pharmacol 2000, 167, 132–139.
- Creppy, E.E.; Schlegel, M.; Röschenthaler, R.; Dirheimer, G. Phenylalanine prevents acute poisoning by ochratoxina in mice. Toxicol. Lett 1980, 6, 77–80.
- Zepnik, H.; Völkel, W.; Dekant, W. Toxicokinetics of the mycotoxin ochratoxin A in F 344 rats after oral administration. Toxicol. Appl. Pharmacol 2003, 192, 36–44.
- Stein, A.F.; Phillips, T.D.; Kubena, L.F.; Harvey, R.B. Renal tubular secretion and reabsorption as factors in ochratoxicosis: Effects of probenecid on nephrotoxicity. J. Toxicol. Environ. Health 1985, 16, 593–605.
- Tsuda, M.; Sekine, T.; Takeda, M.; Cha, S.H.; Kanai, Y.; Kimura, M.; Endou, H. Transport of ochratoxin A by renal multispecific organic anion transporter 1. J. Pharmacol. Exp. Ther 1999, 289, 1301–1305.
- Dai, J.; Wright, M.W.; Manderville, R.A. Ochratoxin a forms a carbon-bonded c8-deoxyguanosine nucleoside adduct: Implications for c8 reactivity by a phenolic radical. J. Am. Chem. Soc 2003, 125, 3716–3717.
- Mantle, P.G.; Faucet-Marquis, V.; Manderville, R.A.; Squillaci, B.; Pfohl-Leszkowicz, A. Structures of covalent adducts between DNA and ochratoxin a: A new factor in debate about genotoxicity and human risk assessment. Chem. Res. Toxicol 2010, 23, 89–98.
- Gautier, J.; Richoz, J.; Welti, D.H.; Markovic, J.; Gremaud, E.; Guengerich, F.P.; Turesky, R.J. Metabolism of ochratoxin A: Absence of formation of genotoxic derivatives by human and rat enzymes. Chem. Res. Toxicol 2001, 14, 34–45.
- Delatour, T.; Mally, A.; Richoz, J.; Özden, S.; Dekant, W.; Ihmels, H.; Otto, D.; Gasparutto, D.; Marin-Kuan, M.; Schilter, B. Absence of 2′-deoxyguanosine-carbon 8-bound ochratoxin A adduct in rat kidney DNA monitored by isotope dilution LC-MS/MS. Mol. Nutr. Food Res 2008, 52, 472–482.
- Mally, A.; Zepnik, H.; Wanek, P.; Eder, E.; Dingley, K.; Ihmels, H.; Völkel, W.; Dekant, W; Ochratoxin, A. Lack of formation of covalent DNA adducts. Chem. Res. Toxicol 2004, 17, 234–242.
- Arbillaga, L.; Azqueta, A.; van Delft, J.H.; Lopez de Cerain, A. In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol. Appl. Pharmacol 2007, 220, 216–224.
- Cavin, C.; Delatour, T.; Marin-Kuan, M.; Holzhäuser, D.; Higgins, L.; Bezençon, C.; Guignard, G.; Junod, S.; Richoz-Payot, J.; Gremaud, E.; Hayes, J.D. Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicol. Sci 2007, 96, 30–39.
- Boesch-Saadatmandi, C.; Loboda, A.; Jozkowicz, A.; Huebbe, P.; Blank, R.; Wolffram, S.; Dulak, J.; Rimbach, G. Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells. Food Chem. Toxicol 2008, 46, 2665–2671.
- Cavin, C.; Delatour, T.; Marin-Kuan, M.; Fenaille, F.; Holzhäuser, D.; Guignard, G.; Bezençon, C.; Piguet, D.; Parisod, V.; Richoz-Payot, J.; et al. Ochratoxin A-mediated DNA and protein damage: Roles of nitrosative and oxidative stresses. Toxicol. Sci 2009, 110, 84–94.
- Cavanagh, J.E.; Weinberg, H.S.; Gold, A.; Sangaiah, R.; Marbury, D.; Glaze, W.H.; Collette, T.W.; Richardson, S.D.; Thruston, A.D., Jr. Ozonation byproducts: Identification of bromohydrins from the ozonation of natural waters with enhanced bromide levels. Environ. Sci. Technol 1992, 26, 1658–1662.
- IARC. Some Chemicals that Cause Tumours of the Kidney or Urinary Bladder in Rodents and Some Other Substances. In IARC Monographs of the Evaluation of Carcinogenic Risks to Humans; The International Agency for Research on Cancer: Lyon, France, 1999; Volume 73.
- El-Sokkary, G.H. Melatonin protects against oxidative stress induced by the kidney carcinogen KBrO3. Neuro Endocrinol. Lett 2000, 21, 461–468.
- Khan, N.; Sultana, S. Abrogation of potassium bromate-induced renal oxidative stress and subsequent cell proliferation response by soy isoflavones in Wistar rats. Toxicology 2004, 201, 173–184.
- Rahman, A.; Ahmed, S.; Khan, N.; Sultana, S.; Athar, M. Glyceryl trinitrate, a nitric oxide donor, suppresses renal oxidant damage caused by potassium bromate. Redox Rep 1999, 4, 263–269.
- Ballmaier, D.; Epe, B. Oxidative DNA damage induced by potassium bromate under cell-free conditions and in mammalian cells. Carcinogenesis 1995, 16, 335–342.
- Umemura, T.; Kanki, K.; Kuroiwa, Y.; Ishii, Y.; Okano, K.; Nohmi, T.; Nishikawa, A.; Hirose, M. In vivo mutagenicity and initiation following oxidative DNA lesion in the kidneys of rats given potassium bromate. Cancer Sci 2006, 97, 829–835.
- Cadenas, S.; Barja, G. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic. Biol. Med 1999, 26, 1531–1537.
- Umemura, T.; Tasaki, M.; Kijima, A.; Okamura, T.; Inoue, T.; Ishii, Y.; Suzuki, Y.; Masui, N.; Nohmi, T.; Nishikawa, A. Possible participation of oxidative stress in causation of cell proliferation and in vivo mutagenicity in kidneys of gpt delta rats treated with potassium bromate. Toxicology 2009, 257, 46–52.
- IARC. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. In IARC Monogr. Eval. Carcinog. Risks Hum; 2002; Volume 82, pp. 1–556.
- Lord, G.M.; Hollstein, M.; Arlt, V.M.; Roufosse, C.; Pusey, C.D.; Cook, T.; Schmeiser, H.H. DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am. J. Kidney Dis 2004, 43, e11–e17.
- Stiborova, M.; Sopko, B.; Hodek, P.; Frei, E.; Schmeiser, H.H.; Hudecek, J. The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen. Cancer Lett 2005, 229, 193–204.
- Fernando, R.C.; Schmeiser, H.H.; Nicklas, W.; Wiessler, M. Detection and quantitation of dG-AAI and dA-AAI adducts by 32P-postlabeling methods in urothelium and exfoliated cells in urine of rats treated with aristolochic acid I. Carcinogenesis 1992, 13, 1835–1839.
- Stiborová, M.; Fernando, R.C.; Schmeiser, H.H.; Frei, E.; Pafau, W.; Wiessler, M. Characterization of DNA adducts formed by aristolochic acids in the target organ (forestomach) of rats by 32P-postlabelling analysis using different chromatographic procedures. Carcinogenesis 1994, 15, 1187–1192.
- Arlt, V.M.; Schmeiser, H.H.; Pfeifer, G.P. Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. Carcinogenesis 2001, 22, 133–140.
- Schmeiser, H.H.; Janssen, J.W.G.; Lyons, J.; Scherf, H.R.; Pfau, W.; Buchmann, A.; Bartram, C.R.; Wiessler, M. Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residues. Cancer Res 1990, 50, 5464–5469.
- Wang, Y.; Meng, F.; Arlt, V.M.; Mei, N.; Chen, T.; Parsons, B.L. Aristolochic acid-induced carcinogenesis examined by ACB-PCR quantification of H-Ras and K-Ras mutant fraction. Mutagenesis 2011, 26, 619–628.
- Duarte, S.C.; Lino, C.M.; Pena, A. Ochratoxin A in feed of food-producing animals: An undesirable mycotoxin with health and performance effects. Veter. Microbiol 2011, 154, 1–13.
- ToxBank. Potassium Bromate, 2012. Available online: http://wiki.toxbank.net/w/index.php/Potassium_Bromate (accessed on 25 April 2013).
- West Coast Analytical Service Aristolochic Acid. Available online: http://www.wcaslab.com/tech/Aristolochic_Acid.htm (accessed on 22 May 2013).
- About Chemistry Chemcial Structure of Chlorform. Available online: http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---C/Chloroform-Chemical-Structure.htm (accessed on 22 May 2013).
- IARC. Preamble to the IARC Monographs, Available online: http://monographs.iarc.fr (accessed on 25 April 2013).
- National Toxicology Program. NTP 11th Report on Carcinogens. Rep. Carcinog 2005, 44, A1–A32.
- Höfer, T.; Gerner, I.; Gundert-Remy, U.; Liebsch, M.; Schulte, A.; Spielmann, H.; Vogel, R.; Wettig, K. Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation. Arch. Toxicol 2004, 78, 549–564.
- Rogiers; Garthoff, B.; Webb, S.; Pauwels, M.; Muller, K.; Devolder, T.; Spielmann, H. The impact of REACH, The report of CONAM/ecopa Chemical Policy Working Group; 2007.
- Martin-Martin, N.; Slattery, C.; McMorrow, T.; Ryan, M.P. TGF-β1 mediates sirolimus and cyclosporine A-induced alteration of barrier function in renal epithelial cells via a noncanonical ERK1/2 signaling pathway. Am. J. Physiol. Renal Physiol 2011, 301, F1281–F1292.
- Martin-Martin, N.; Dan, Q.; Amoozadeh, Y.; Waheed, F.; McMorrow, T.; Ryan, M.P.; Szászi, K. RhoA and Rho kinase mediate cyclosporine A and sirolimus-induced barrier tightening in renal proximal tubular cells. Int. J. Biochem. Cell Biol 2012, 44, 178–188.
- Jennings, P.; Aydin, S.; Bennett, J.; McBride, R.; Weiland, C.; Tuite, N.; Gruber, L.N.; Perco, P.; Gaora, P. Ó.; Ellinger-Ziegelbauer, H. Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol. In Vitro 2009, 23, 486–499.
- Radford, R.; Slattery, C.; Jennings, P.; Blaque, O.; Pfaller, W.; Gmuender, H.; van Delft, J.; Ryan, M.P.; McMorrow, T. Carcinogens induce loss of the primary cilium in human renal proximal tubular epithelial cells independently of effects on the cell cycle. Am. J. Physiol. Renal Physiol 2012, 302, F905–F916.
- Ellis, J.K.; Athersuch, T.J.; Cavill, R.; Radford, R.; Slattery, C.; Jennings, P.; McMorrow, T.; Ryan, M.P.; Ebbels, T.M.D.; Keun, H.C. Metabolic response to low-level toxicant exposure in a novel renal tubule epithelial cell system. Mol. Biosyst 2011, 7, 247–257.
- Jennings, P.; Weiland, C.; Limonciel, A.; Bloch, K.M.; Radford, R.; Aschauer, L.; McMorrow, T.; Wilmes, A.; Pfaller, W.; Ahr, H.J.; et al. Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch. Toxicol 2011, doi:10.1007/s00204-011-0780-4..
- Ohmori, K.; Sasaki, K.; Asada, S.; Tanaka, N.; Umeda, M. An assay method for the prediction of tumor promoting potential of chemicals by the use of Bhas 42 cells. Mutat. Res 2004, 557, 191–202.
- Tsuchiya, T.; Umeda, M.; Tanaka, N.; Sakai, A.; Nishiyama, H.; Yoshimura, I.; Ajimi, S.; Asada, S.; Asakura, M.; Baba, H.; et al. Application of the improved BALB/c 3T3 cell transformation assay to the examination of the initiating and promoting activities of chemicals: The second interlaboratory collaborative study by the non-genotoxic carcinogen study group of Japan. Altern. Lab. Anim 2010, 38, 11–27.
© 2013 by the authors; licensee MDPI, Basel, Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).