Metabolism of territrem B and C in liver microsomes from 14-wk-old Wistar rats is catalyzed by cytochrome P-450 3A.
The metabolism of territrem B (TRB) and territrem C (TRC) in liver microsomes of 14-wk-old male and female Wistar rats was investigated. Metabolism of TRB to 4beta-hydroxylmethyl-4beta-demethylterritrem B (MB2), O-demethylation of the methoxy group of the aromatic moiety of TRB to form MB4 (same structure as TRC), and metabolism of TRC to 4beta-hydroxylmethyl-4beta-demethylterritrem C (MC) were observed in both genders. However, the amounts of MB2, MB4, and MC formed in females were much lower than in males. To investigate which cytochrome P-450 (CYP450) isoforms were involved in each step, four CYP450 isotype-specific inhibitors (furafylline, orphenadrine, cimetidine, and troleandomycin) and antibodies against CYP1A1, CYP2B1, CYP2C11, or CYP3A2 were used. Formation of MB2, MB4, and MC was markedly inhibited by cimetidine and troleandomycin, but less by furafylline and orphenadrine. Anti-CYP3A2 antibody completely inhibited MB, MB, and MC formation, while antibodies against CYP1A1, CYP2B1, or CYP2C11 produced no marked effect. Of the seven tested supersomes from baculovirus-transformed insect cells expressing rat CYP450 isoforms (1Al, 1A2, 2B1, 2C11, 2C12, 3A1, and 3A2), only those expressing CYP3A1 and CYP3A2 metabolized TRB and TRC. The amounts of MB2, MB4, and MC formed by male and female rat liver microsome preparations were related to the testosterone 6beta-hydroxylase activity and CYP3A1/2 protein content of the preparation. Immunoblotting showed that CYP3A1 was expressed in both genders, but at different levels, while CYP3A2 was only expressed in males. These results suggest that the formation of MB2, MB4, and MC in liver microsomes from 14-wk-old rats of either gender is mediated by CYP3A1 and CYP3A2.
Peng
Fu-Chuo
FC
Institute of Toxicology, College of Medicine, National Taiwan University, Republic of China, Taipei, Taiwan, ROC. fcpeng@ha.mc.ntu.edu.tw
Chen
Pei-Chun
PC
Jeng
Yea-Jen
YJ
Edwards
Robert J
RJ
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000494:pharmacology*; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009183:Mycotoxins; D010089:Oxidoreductases, N-Demethylating / Q000494:pharmacology*; D011714:Pyrans / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D009183:Mycotoxins; D011714:Pyrans; C040405:territrem B; C040403:territrem C; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating