Cytochrome P-4503A1 catalyzes the formation of MA1 from territrem a in liver microsomes of 7-week-old female Wistar rats.
Liver microsomal territrem A (TRA) metabolism was studied in 7-wk-old female Wistar rats. Pretreatment with phenobarbital (PB) or dexamethasone (DEX) resulted in a significant increase in 4 beta-hydroxymethyl-4 beta-demethylterritrem A (MA1) production. SKF 525A (0.025 and 0.05 mM), a general cytochrome P-450 (CYP450) inhibitor, blocked MA1 formation in liver microsomes from PB-pretreated female rats. Anti-CYP2B antibody had no marked effect on MA1 formation, although orphenadrine (0.5 mM), which inhibits CYP2B, blocked MA1 formation in liver microsomes from PB-treated female rats. An immunoinhibition study showed that anti-CYP3A2 antibody reduced MA1 formation to nondetectable levels in liver microsomes from PB-treated female rats. Furthermore, immunoblotting showed that CYP3A1 protein was expressed in 7-wk-old female rat and only MA1 was formed from TRA using supersomes from CYP3A1-expressing baculovirus-infected insect cells. Further, Western blot analysis indicated that CYP3A2 protein was expressed in 2-wk-old rats of both sexes and 7-wk-old male rats, and 3 metabolites of TRA, such as MA1, MAX, and MA2, were formed using supersomes from CYP3A2-expressing baculovirus-infected insect cells. These results suggest that MA1 formation in liver microsomes of 7-wk-old female Wistar rats is mediated by CYP3A1.
Lin Wu
Shiuan-Woei
SW
Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1 Jen-Ai Road, Taipei, Taiwan, Republic of China.
Jean
Wen-Chi
WC
Peng
Fu-Chuo
FC
Edwards
Robert J
RJ
D000818:Animals; D000906:Antibodies; D001189:Aryl Hydrocarbon Hydroxylases / Q000494:pharmacology*; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009183:Mycotoxins / Q000378:metabolism*; D011714:Pyrans / Q000378:metabolism*; D011753:Pyrones / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors
C473658:4-hydroxymethyl-4-demethylterritrem A; D000906:Antibodies; D009183:Mycotoxins; D011714:Pyrans; D011753:Pyrones; C040404:territrem A; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A