Abstract
Minipigs represent a good animal model because of the physiologic and anatomic similarities they share with humans. Three cytochrome P450 (CYP) 3A isozymes, CYP3A22, CYP3A29, and CYP3A46, have recently been reported to be expressed in Bama minipigs, which have limited data relating to their metabolic characteristics. In the present study, Bama minipig CYP3A22, CYP3A29, and CYP3A46 were recombinantly expressed and their metabolic manners were compared with those of human CYP3A4 and CYP3A5 and also human and Bama minipig liver microsomes. The results indicated Bama minipigs and human CYP3A enzymes showed similar metabolic kinetics and metabolite profiles using testosterone, midazolam, and nifedipine as substrates. However, the differences in amino acid sequences change the elimination velocity and metabolic preference of CYP3A enzymes to their substrates. It was demonstrated that CYP3A29, CYP3A4, and CYP3A5 were the most active enzymes for all reactions, whereas CYP3A46 was the least active enzyme. Substrate-dependent metabolism characteristics between human and Bama minipig CYP3A isoenzymes exist.
Footnotes
- Received April 3, 2015.
- Accepted June 12, 2015.
Y.B., Q.Y., and H.S. contributed equally to the work.
This study was supported by the National Natural Science Foundation of China [Grant 81173126] and National Major Projects of China [Grant 2012ZX09506001-004], National Science and Technology Major Project of China [Grant 2011ZXJ09201-301], and National Science and Technology Infrastructure Program of China [Grant 2012BAI39B04].
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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