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3. Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics.

Author

Minegishi, Genki, Kobayashi, Yuka, Fujikura, Mayu, Sano, Ayane, Kazuki, Yasuhiro, and Kobayashi, Kaoru

Subjects
*CHOLIC acid, *GENE expression, *CYTOCHROME P-450 CYP3A, *CHOLESTEROL, *LIVER microsomes, *HYDROXYCHOLESTEROLS
Abstract

Human cytochrome P450 3A4 (CYP3A4) is a drug‐metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human‐like regulation of the coding genes. A normal diet (ND, CE‐2), CE‐2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE‐2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Metabolic Disposition of Triazolam and Clobazam in Humanized CYP3A Mice with a Double-Knockout Background of Mouse Cyp2candCyp3aGenes

Author

Kobayashi, Kaoru, Minegishi, Genki, Kuriyama, Nina, Miyajima, Atsushi, Abe, Satoshi, Kazuki, Kanako, and Kazuki, Yasuhiro

Abstract

Knockout (KO) of mouse Cyp3agenes increases the expression of hepatic CYP2C enzymes, which can metabolize triazolam, a typical substrate of human CYP3A. There is still marked formation of 1’-hydroxytriazolam in Cyp3a-KO (3aKO) mice after triazolam dosing. Here, we generated a new model of humanized CYP3A (hCYP3A) mice with a double-KO background of Cyp3aand Cyp2cgenes (2c3aKO), and we examined the metabolic profiles of triazolam in wild-type (WT), 2c3aKO, and hCYP3A/2c3aKO mice in vitroand in vivo. In vitrostudies using liver microsomes showed that the formation of 1’-hydroxytriazolam in 2c3aKO mice was less than 8% of that in WT mice. The formation rate of 1’-hydroxytriazolam in hCYP3A/2c3aKO mice was eightfold higher than that in 2c3aKO mice. In vivostudies showed that area under the curve (AUC) of 1’-hydroxytriazolam in 2c3aKO mice was less than 3% of that in WT mice. The AUC of 1’-hydroxytriazolam in hCYP3A/2c3aKO mice was sixfold higher than that in 2c3aKO mice. These results showed that formation of 1’-hydroxytriazolam was significantly decreased in 2c3aKO mice. Metabolic functions of human CYP3A enzymes were distinctly found in hCYP3A mice with the 2c3aKO background. Moreover, hCYP3A/2c3aKO mice treated with clobazam showed human CYP3A-mediated formation of desmethylclobazam and prolonged elimination of desmethylclobazam, which is found in poor metabolizers of CYP2C19. The novel hCYP3A mouse model without mouse Cyp2cand Cyp3agenes (hCYP3A/2c3aKO) is expected to be useful to evaluate human CYP3A-mediated metabolism in vivo.SIGNIFICANT STATEMENTHumanized CYP3A (hCYP3A/2c3aKO) mice with a background of double knockout (KO) for mouse Cyp2cand Cyp3agenes were generated. Although CYP2C enzymes played a compensatory role in the metabolism of triazolam to 1’-hydroxytriazolam in the previous hCYP3A/3aKO mice with Cyp2cgenes, the novel hCYP3A/2c3aKO mice clearly showed functions of human CYP3A enzymes introduced by chromosome engineering technology.

Published
2023
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7. Comparison of the hepatic metabolism of triazolam in wild-type andCyp3a-knockout mice for understanding CYP3A-mediated metabolism inCYP3A-humanised mice in vivo

Author

Minegishi, Genki, Kazuki, Yasuhiro, Yamasaki, Yuki, Fuka Okuya, Akita, Hidetaka, Oshimura, Mitsuo, and Kobayashi, Kaoru

Abstract

1. To investigate cytochrome P450 3A (CYP3A)-mediated metabolism in vivo, plasma concentrations of triazolam (TRZ) are often monitored as a CYP3A marker in CYP3A-humanised mice. However, it has not been determined whether plasma concentrations of TRZ after intravenous administration can reflect hepatic CYP3A activity in CYP3A-humanised mice. 2. Firstly, we investigated the pharmacokinetics of TRZ in wild-type and Cyp3a-knockout (Cyp3a-KO) mice. Plasma concentration profiles of TRZ and α-hydroxy (OH) TRZ were very similar in wild-type and Cyp3a-KO mice. On the other hand, AUC of 4-OH TRZ in Cyp3a-KO mice was significantly lower than that in wild-type mice. Pregnenolone 16α-carbonitrile (PCN) decreased the areas under the plasma concentration-time curves (AUCs) of TRZ and α-OH TRZ in both groups. There was no significant effect of PCN on AUC of 4-OH TRZ in Cyp3a-KO mice. 3. Next, we verified that AUC of 4-OH TRZ in CYP3A-humanised mice was higher than that in Cyp3a-KO mice, although the difference was not significant. 4. In conclusion, plasma concentrations of 4-OH TRZ, but not those of TRZ and α-OH TRZ, might reflect hepatic CYP3A activity in mice in vivo. These results provide important insights for in vivo studies using a CYP3A-humanised model.

Published
2019
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8. Comparison of the hepatic metabolism of triazolam in wild-type andCyp3a-knockout mice for understanding CYP3A-mediated metabolism inCYP3A-humanised mice

Author

Minegishi, Genki, Kazuki, Yasuhiro, Yamasaki, Yuki, Okuya, Fuka, Akita, Hidetaka, Oshimura, Mitsuo, and Kobayashi, Kaoru

Subjects
Male, Pregnenolone Carbonitrile, Triazolam, CYP3A, Health, Toxicology and Mutagenesis, Pharmacology, Toxicology, 030226 pharmacology & pharmacy, Biochemistry, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Cytochrome P-450 Enzyme System, In vivo, medicine, Animals, Cytochrome P-450 CYP3A, Humans, Mice, Knockout, Mice, Inbred ICR, Chemistry, Wild type, General Medicine, Liver, 030220 oncology & carcinogenesis, Area Under Curve, Knockout mouse, Pregnenolone, Microsomes, Liver, Drug metabolism, medicine.drug
Abstract

1. To investigate cytochrome P450 3A (CYP3A)-mediated metabolism in vivo, plasma concentrations of triazolam (TRZ) are often monitored as a CYP3A marker in CYP3A-humanised mice. However, it has not been determined whether plasma concentrations of TRZ after intravenous administration can reflect hepatic CYP3A activity in CYP3A-humanised mice. 2. Firstly, we investigated the pharmacokinetics of TRZ in wild-type and Cyp3a-knockout (Cyp3a-KO) mice. Plasma concentration profiles of TRZ and α-hydroxy (OH) TRZ were very similar in wild-type and Cyp3a-KO mice. On the other hand, AUC of 4-OH TRZ in Cyp3a-KO mice was significantly lower than that in wild-type mice. Pregnenolone 16α-carbonitrile (PCN) decreased the areas under the plasma concentration-time curves (AUCs) of TRZ and α-OH TRZ in both groups. There was no significant effect of PCN on AUC of 4-OH TRZ in Cyp3a-KO mice. 3. Next, we verified that AUC of 4-OH TRZ in CYP3A-humanised mice was higher than that in Cyp3a-KO mice, although the difference was not significant. 4. In conclusion, plasma concentrations of 4-OH TRZ, but not those of TRZ and α-OH TRZ, might reflect hepatic CYP3A activity in mice in vivo. These results provide important insights for in vivo studies using a CYP3A-humanised model.

Published
2018

9. CYP3A4 Induction in the Liver and Intestine of Pregnane X Receptor/CYP3A-Humanized Mice: Approaches by Mass Spectrometry Imaging and Portal Blood Analysis

Author

Kobayashi, Kaoru, primary, Kuze, Jiro, additional, Abe, Satoshi, additional, Takehara, Shoko, additional, Minegishi, Genki, additional, Igarashi, Katsuhide, additional, Kitajima, Satoshi, additional, Kanno, Jun, additional, Yamamoto, Takushi, additional, Oshimura, Mitsuo, additional, and Kazuki, Yasuhiro, additional

Published
2019
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11. Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans

Author

Yamasaki, Yuki, primary, Kobayashi, Kaoru, additional, Okuya, Fuka, additional, Kajitani, Naoyo, additional, Kazuki, Kanako, additional, Abe, Satoshi, additional, Takehara, Shoko, additional, Ito, Shingo, additional, Ogata, Seiryo, additional, Uemura, Tatsuki, additional, Ohtsuki, Sumio, additional, Minegishi, Genki, additional, Akita, Hidetaka, additional, Chiba, Kan, additional, Oshimura, Mitsuo, additional, and Kazuki, Yasuhiro, additional

Published
2018
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