Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. Animals
2.3. CYP450 mRNA Levels
2.3.1. Isolation of RNA and Preparation of cDNA
2.3.2. RT-qPCR Analysis
2.4. In Vitro CYP450 Metabolism in Liver and Extra-Hepatic Organs
2.4.1. Preparation of Microsomes
2.4.2. Effects of the HFD on Hepatic and Extra-Hepatic cyp450 Activities
2.5. High Performance Chromatography–Mass Spectrometry Analytical Methods
2.5.1. Chromatographic Conditions for the Metabolites of Bupropion, Midazolam and Ebastine
2.5.2. Chromatographic Conditions for the Metabolites of Chlorzoxazone, Tolbutamide, Dodecanoic Acid, Bufuralol and Repaglinide
2.6. Statistical Analysis
3. Results
3.1. Animal Model
3.2. Effects of HFD on cyp450 mRNA Expression Levels
3.2.1. General Pattern of cyp450 Expression
3.2.2. Modulation of cyp450 mRNA Expression by HFD
3.3. Modulation of cyp450 Hepatic Activities by DIO Mouse as a Model of T2D
3.3.1. Hepatic Activities
3.3.2. Extra-Hepatic Activities
4. Discussion
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
DIO | diet-induced obesity |
DMSO | dimethyl sulfoxide |
G6P | glucose-6-phosphate |
G6PD | glucose-6-phosphate dehydrogenase |
HDR | high-diet responders |
HFD | high-fat diet |
IFN-γ | interferon-γ |
IL-1β | interleukin-1β |
IL-6 | interleukin-6 |
LC-MS/MS | liquid chromatography–tandem mass spectrometry |
LDR | low-diet responders |
NADP | Nicotinamide-Adenine Dinucleotide Phosphate |
P450 | cytochrome P450 |
PMSF | phenylmethanesulfonyl |
RT-qPCR | real time quantitative polymerase chain reaction |
T2D | type 2 diabetes |
VHDR | very high-diet responders |
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Tissue | Diet | cyp2b9 | cyp2b10 | cyp2c29 | cyp2c37 | cyp2c39 | cyp2c40 | cyp2d9 | cyp2d22 | cyp2e1 | cyp2j5 | cyp2j6 | cyp3a11 | cyp3a13 | cyp3a25 | cyp4a10 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Liver | ND | 0.01 | 0.02 | 0.49 | 1.31 | 0.01 | 0.44 | 0.55 | 0.53 | 0.56 | 0.98 | 1.08 | 0.58 | 2.40 | 0.44 | 1.25 |
LDR | 4.89 * | NQ | 0.25 * | 1.77 | 0.01 | 0.20 | 0.81 | 0.59 | 1.02 | 1.05 | 0.88 | 0.04 ᵵ | 3.07 | 0.17 | 1.22 | |
HDR | 8.51 ᵵ | 0.03 | 0.30 | 2.15 | 0.02 ** | 0.37 | 0.71 | 1.03 | 0.79 | 0.90 | 1.09 | 0.04 ᵵ | 2.96 | 0.21 | 3.72 | |
Kidney | ND | ND | 0.54 | 2.35 | ND | ND | 8.62 | 1.65 | 1.32 | 1.28 | 4.89 | 4.56 | 1.41 | 1.37 | 2.00 | 1.42 |
LDR | ND | 0.46 | 3.08 | ND | ND | 3.08 | 1.35 | 1.38 | 1.29 | 4.68 | 4.62 | 0.57 | 2.12 | 1.79 | 1.13 | |
HDR | ND | 0.42 | 1.59 | ND | ND | 5.92 | 1.65 | 1.50 | 1.29 | 4.18 | 4.03 | 0.72 | 2.41 | 0.95 | 2.43 | |
Heart | ND | ND | 1.21 | 0.26 | ND | ND | ND | 0.05 | 3.24 | 0.96 | 0.09 | 2.19 | ND | NQ | ND | 1.09 |
LDR | ND | 2.16 | 0.49 | ND | ND | ND | 0.07 | 3.40 | 0.62 | 0.19 | 1.85 | ND | NQ | ND | 2.15 | |
HDR | ND | 1.68 | 0.30 | ND | ND | ND | 0.07 | 5.03 | 0.51 * | 0.19 | 1.67 | ND | NQ | NQ | 1.47 | |
Lung | ND | ND | 0.73 | 1.11 | ND | ND | ND | 0.07 | 2.06 | 0.21 | 0.13 | 1.20 | ND | 3.26 | 0.06 | 3.28 |
LDR | ND | 1.66 ᵵ | 2.96 | ND | ND | ND | 0.08 | 2.05 | 0.33 ** | 0.47 | 1.88 | ND | 8.15 ** | 0.07 | 9.90 * | |
HDR | ND | 1.17 ** | 1.00 | ND | ND | ND | ND | 5.76 | 0.32 * | 0.83 | 1.69 | ND | 5.39 | 0.11 | 3.43 |
Liver | ND | LDR | HDR |
---|---|---|---|
(nmol/mg protein/min) | |||
Bupropion → Hydroxybupropion | 0.030 ± 0.004 | 0.030 ± 0.004 | 0.023 ± 0.002 ** |
Tolbutamide → Hydroxytolbutamide | 0.22 ± 0.01 | 0.15 ± 0.01 ᵵ | 0.17 ± 0.02 ᵵ |
Repaglinide → M1-repaglinide | 0.050 ± 0.006 | 0.007 ± 0.002 ᵵ | 0.0081 ± 0.0003 ᵵ |
Repaglinide → Hydroxyrepaglinide | 0.0020 ± 0.0001 | 0.0010 ± 0.0002 ᵵ | 0.0013 ± 0.0004 ** |
Bufuralol → Hydroxybufuralol | 0.26 ± 0.05 | 0.19 ± 0.06 | 0.21 ± 0.06 |
Chlorzoxazone → Hydroxychlorzoxazone | 2.0 ± 0.1 | 2.4 ± 0.3 ** | 1.9 ± 0.1 |
Ebastine → Hydroxyebastine and carebastine | 0.044 ± 0.007 | 0.07 ± 0.01 ᵵ | 0.057 ± 0.008 * |
Midazolam → 1′-hydroxymidazolam | 0.32 ± 0.06 | 0.06 ± 0.01 ᵵ | 0.06 ± 0.01 ᵵ |
Dodecanoic acid → 12-hydroxydecanoic acid | 0.19 ± 0.03 | 0.27 ± 0.05 | 0.3 ± 0.1 * |
(A) | |||
Kidney | ND | LDR | HDR |
(pmol/mg protein/min) | |||
Bupropion → Hydroxybupropion | 12.5 ± 0.6 | 12.6 ± 0.4 | 8 ± 1 ** |
Tolbutamide → Hydroxytolbutamide | 1.76 ± 0.06 | 2.63 ± 0.01 ᵵ | 2.10 ± 0.04 ** |
Repaglinide → M1-repaglinide | 0.09 ± 0.01 | 0.105 ± 0.002 | 0.073 ± 0.003 |
Bufuralol → Hydroxybufuralol | 3.50 ± 0.03 | 7.7 ± 0.4 ᵵ | 7.4 ± 0.2 ᵵ |
Chlorzoxazone → Hydroxychlorzoxazone | 130 ± 6 | 144.6 ± 0.2 ** | 108 ± 3 ** |
Ebastine → Hydroxyebastine and carebastine | 13 ± 1 | 13.9 ± 0.3 | 9 ± 1 * |
Midazolam → 1′-hydroxymidazolam | 0.24 ± 0.02 | 0.065 ± 0.002 ᵵ | 0.047 ± 0.008 ᵵ |
Dodecanoic acid → 12-hydroxydecanoic acid | 173 ± 27 | 193 ± 3 | 118 ± 24 * |
(B) | |||
Lung | ND | LDR | HDR |
(pmol/mg protein/min) | |||
Bupropion → Hydroxybupropion | 538 ± 26 | 476 ± 4 * | 467 ± 14 ** |
Tolbutamide → Hydroxytolbutamide | 0.64 ± 0.02 | 0.59 ± 0.03 | 0.54 ± 0.01 ** |
Repaglinide → M1-repaglinide | N/F | N/F | N/F |
Bufuralol → Hydroxybufuralol | 0.59 ± 0.02 | 0.55 ± 0.02 * | 0.425 ± 0.001 ᵵ |
Chlorzoxazone → Hydroxychlorzoxazone | 477 ± 16 | 629 ± 79 ** | 535 ± 19 |
Ebastine → Hydroxyebastine and carebastine | 17 ± 1 | 12.6 ± 0.9 * | 7 ± 3 ᵵ |
Midazolam → 1′-hydroxymidazolam | 0.51 ± 0.01 | 0.47 ± 0.04 | 0.51 ± 0.01 |
Dodecanoic acid → 12-hydroxydecanoic acid | 93 ± 6 | 78 ± 1 * | 68 ± 4 ᵵ |
(C) | |||
Heart | ND | LDR | HDR |
(pmol/mg protein/min) | |||
Bupropion → Hydroxybupropion | 0.15 ± 0.01 | 0.037 ± 0.004 ᵵ | 0.025 ± 0.003 ᵵ |
Tolbutamide → Hydroxytolbutamide | N/F | N/F | N/F |
Repaglinide → M1-repaglinide | N/A | N/A | N/A |
Bufuralol → Hydroxybufuralol | N/A | N/A | N/A |
Chlorzoxazone → Hydroxychlorzoxazone | 1.7 ± 0.1 | 1.2 ± 0.1 * | 1.7 ± 0.2 |
Ebastine → Hydroxyebastine and carebastine | 0.8 ± 0.1 | 0.76 ± 0.06 | 0.78 ± 0.06 |
Midazolam → 1′-hydroxymidazolam | N/F | N/F | N/F |
Dodecanoic acid → 12-hydroxydecanoic acid | N/F | N/F | N/F |
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Maximos, S.; Chamoun, M.; Gravel, S.; Turgeon, J.; Michaud, V. Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues. Pharmaceutics 2017, 9, 40. https://doi.org/10.3390/pharmaceutics9040040
Maximos S, Chamoun M, Gravel S, Turgeon J, Michaud V. Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues. Pharmaceutics. 2017; 9(4):40. https://doi.org/10.3390/pharmaceutics9040040
Chicago/Turabian StyleMaximos, Sarah, Michel Chamoun, Sophie Gravel, Jacques Turgeon, and Veronique Michaud. 2017. "Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues" Pharmaceutics 9, no. 4: 40. https://doi.org/10.3390/pharmaceutics9040040