Liver microsomal cytochrome P450 3A-dependent drug oxidation activities in individual dogs

Abstract

1. Drug oxidations are mediated mainly by cytochromes P450 (P450s or CYPs). CYP3As are an important P450 subfamily and include liver-specific CYP3A12 and intestine-specific CYP3A98 in dogs. Individual differences in drug oxidation activities were investigated, including correlations with immunoreactive CYP3A protein intensities and CYP3A mRNA expression levels in livers.

2. Pooled and individual dog liver microsomes showed activities towards nifedipine, midazolam, alprazolam, and estradiol, but the levels of catalytic activities varied approximately twofold among the individual dogs. One dog harboured a CYP1A2 variant causing protein deletion but showed higher activities than the other dogs towards nifedipine oxidation, midazolam 1′-hydroxylation, alprazolam 4-hydroxylation, estradiol 16α-hydroxylation activities, and caffeine C₈-hydroxylation; the latter is used as a reference reaction for CYP1A.

3. In individual dog liver microsomes, the intensities of the immunochemical bands with anti-human CYP3A4 and anti-rat CYP3A2 antibodies along with CYP3A12 and CYP3A26 mRNA expression levels showed good correlations (p < 0.05) with nifedipine oxidation, midazolam 1′- and 4-hydroxylation, alprazolam 1′- and 4-hydroxylation, and estradiol 16α-hydroxylation activities.

4. These results suggest that the oxidation activities of dog liver microsomes towards nifedipine and other typical CYP3A-catalyzed drugs exhibit approximately twofold individual differences and were predominantly mediated by liver-specific CYP3A12 in the dogs.

Keywords:

• P450 3A12
• P450 3A26
• P450 1A2
• oestradiol
• caffeine

Acknowledgments

We thank Drs. Yuki Fujiki, Asuka Oguchi, Koichiro Adachi, and Makiko Shimizu for their support of this work. The authors also thank David Smallbones for copyediting a draft of this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported partly by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research 20K06434.