Evaluation of mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mouse with humanized liver

Abstract

The hepatic mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mise with almost-completely humanized liver (replacement index: 71–89%) was investigated. The mRNAs of 58 human phase I enzymes, 26 human phase II enzymes, 23 human transporters, and five mouse Cyps were measured in the chimeric mice with humanized liver generated using hepatocytes from a Japanese donor. The mRNA expression of 52 human phase I enzymes, which includes 20 human CYPs, 26 human phase II enzymes and 21 human transporters was ascertained in the chimeric mouse liver. Among them, the expression of the target mRNAs vital for liver function such as the metabolism and secretion of endogenous compounds appeared to be maintained. The central value for the expression ratio in all target genes in chimeric mouse liver to the donor liver was 0.46, which was lower than the substitution rate of chimeric mouse liver by donor liver. The ratio of mouse Cyp mRNA expression of chimeric mouse liver to that of control mouse liver was 0.19 or less, except for that of Cyp2b10. There were good correlations between the mRNA expression levels of human hepatic albumin gene, the values of the rate of replacement of mouse liver by human liver, and the human blood albumin concentration in the chimeric mice. The chimeric mice with humanized liver may be a useful tool for the evaluation of drug–drug interactions such as the inhibition and induction of drug-metabolizing enzymes and transporters.

Kewords: :

• Chimeric mouse
• humanized liver
• transporters

Acknowledgements

This work was supported in part by Hiroshima Tissue Regeneration Project, Collaboration of Regional Entities for the Advancement of Technological Excellence (CREATE), Japan Science and Technology Agency (JST), and by Research in Advanced Medical Technology, Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare of Japan. We acknowledge Mr Brent Bell for reviewing the manuscript.