Phase I and Phase II Xenobiotic-Metabolizing Enzymes: Structure, Function, and Regulation

Topic Information

Dear Colleagues,

Enzymes that catalyse the biotransformation of foreign compounds are generally referred to as xenobiotics‐metabolizing enzymes (XMEs). XMEs catalyse functionalization and conjugation reactions that lead to the conversion of xenobiotics to more water-soluble compounds, facilitating the excretion of xenobiotics from the cell. The biotransformation reactions of xenobiotics are classified into two sequential phases: phase I (oxidation, reduction, and hydrolysis reactions) and phase II (conjugation reactions). Phase I reactions expose or introduce a functional group (—OH, —NH₂, —SH, or —COOH), and they usually only result in a small increase in hydrophilicity. Phase II biotransformation reactions include glucuronidation, sulfation, acetylation, methylation, and conjugation with the tripeptide glutathione, which usually result in increased hydrophilicity and elimination. XMEs typically have highly plastic active sites that can accommodate a variety of substrates. It is well established that the combination of phase I and phase II XMEs and the resulting balance between metabolic activation and detoxification may be critical for the toxicity of xenobiotics. The human genome contains a large number of genes that encode XMEs. Genetic and functional variations in these genes are substantial and have complex consequences that depend, for example, on whether enzyme structure or expression is affected, or whether the metabolites produced are pharmacologically or toxicologically active. XMEs are often coordinately induced by a variety of chemical agents through the Keap1-Nrf2-ARE signalling pathway, which plays a critical role in the expression of many XMEs and acts as a sensor of oxidative stress. For this topic, we welcome reviews and/or original research papers in the field of XMEs in various organisms (humans, animals, invertebrates, plants, etc.). XMEs are key players among the many enzyme and transporter systems affecting the therapeutic or toxic effects of a xenobiotic. Structural/functional information about the XME-mediated biotransformation of xenobiotics is just one piece of a bigger puzzle when studying toxic outcomes in humans or environmental species. Researchers are cordially invited to submit studies relevant to these topics.

Prof. Dr. Nikolaos Labrou
Prof. Dr. Anastassios C. Papageorgiou
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
BioChem biochem	-	-	2021	21.7 Days	CHF 1000	Submit
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700	Submit
Journal of Xenobiotics jox	6.8	5.3	2011	28 Days	CHF 1600	Submit
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900	Submit

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Open AccessArticle

Genetic Interactions of Phase II Xenobiotic-Metabolizing Enzymes GSTO1 and GCLC in Relation to Alcohol Abuse and Psoriasis Risk

by Roman Saranyuk, Olga Bushueva, Ekaterina Efanova, Maria Solodilova, Mikhail Churnosov and Alexey Polonikov

J. Xenobiot. 2025, 15(2), 60; https://doi.org/10.3390/jox15020060 - 20 Apr 2025

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Abstract

The present pilot study aimed to investigate whether common single nucleotide polymorphisms (SNPs) in the gene encoding glutathione S-transferase omega 1 (GSTO1), both individually and in combination with variants of the catalytic subunit of the glutamate cysteine ligase (GCLC) [...] Read more.

The present pilot study aimed to investigate whether common single nucleotide polymorphisms (SNPs) in the gene encoding glutathione S-transferase omega 1 (GSTO1), both individually and in combination with variants of the catalytic subunit of the glutamate cysteine ligase (GCLC) gene and environmental risk factors, are associated with the risk of psoriasis. The research included a total of 944 participants, comprising 474 individuals diagnosed with psoriasis and 470 healthy control subjects. Five common SNPs in the GSTO1 gene—specifically, rs11191736, rs34040810, rs2289964, rs11191979, and rs187304410—were genotyped in the study groups using the MassARRAY-4 system. The allele rs187304410-A (OR = 0.19, 95% CI 0.04–0.86, Pperm = 0.02) and the genotype rs187304410-G/A (OR = 0.19, 95% CI 0.04–0.85, Pperm = 0.01) were found to be associated with psoriasis in females. The model-based multifactor dimensionality reduction approach facilitated the identification of higher-order epistatic interactions between the variants of the GSTO1 and GCLC genes (Pperm < 0.0001). These interactions, along with the risk factor of alcohol abuse, collectively contribute to the pathogenesis of psoriasis. This study is the first to demonstrate that polymorphisms in the GSTO1 gene, both individually and in combination with variants of the GCLC gene and alcohol abuse, are associated with an increased risk of psoriasis. Full article

(This article belongs to the Topic Phase I and Phase II Xenobiotic-Metabolizing Enzymes: Structure, Function, and Regulation)

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Open AccessReview

Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation

by Pradeepraj Durairaj and Zixiang Leonardo Liu

J. Xenobiot. 2025, 15(2), 44; https://doi.org/10.3390/jox15020044 - 14 Mar 2025

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Abstract

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain’s complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling [...] Read more.

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain’s complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling pathways, modulates enzyme functions, and leads to distinct CYP gene expression and regulation patterns compared to the liver. Despite their relatively low levels of expression, brain CYPs exert significant influence on drug responses, neurotoxin susceptibility, behavior, and neurological disease risk. These enzymes are essential for maintaining brain homeostasis, mediating cholesterol turnover, and synthesizing and metabolizing neurochemicals, neurosteroids, and neurotransmitters. Moreover, they are key participants in oxidative stress responses, neuroprotection, and the regulation of inflammation. In addition to their roles in metabolizing psychotropic drugs, substances of abuse, and endogenous compounds, brain CYPs impact drug efficacy, safety, and resistance, underscoring their importance beyond traditional drug metabolism. Their involvement in critical physiological processes also links them to neuroprotection, with significant implications for the onset and progression of neurodegenerative diseases. Understanding the roles of cerebral CYP enzymes is vital for advancing neuroprotective strategies, personalizing treatments for brain disorders, and developing CNS-targeting therapeutics. This review explores the emerging roles of CYP enzymes, particularly those within the CYP1–3 and CYP46 families, highlighting their functional diversity and the pathological consequences of their dysregulation on neurological health. It also examines the potential of cerebral CYP-based biomarkers to improve the diagnosis and treatment of neurodegenerative disorders, offering new avenues for therapeutic innovation. Full article

(This article belongs to the Topic Phase I and Phase II Xenobiotic-Metabolizing Enzymes: Structure, Function, and Regulation)

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