Predicting the contribution of rat cytochrome P-450 3A1, 3A2 and human cytochrome P-450 3A4, 3A5 to territrem a 4beta-C hydroxylation using the relative activity factor.
The relative activity factor (RAF) was used to predict the contribution of different cytochrome P-450 (CYP) 3A isoforms (3A1 and 3A2 in rat liver microsomes and 3A4 and 3A5 in human liver microsomes) to 4beta-C hydroxylation of territrem A (TRA). Seven recombinant rat and eight recombinant human CYP450 isoforms, five rat liver microsomes, and seven human liver microsomes were assessed. In liver microsomes from five male Wistar rats, TRA 4beta-C hydroxylation activity significantly correlated with CYP3A1/2 activity, while, in liver microsomes from seven humans, there was marked correlation with CYP3A4 activity. Immunoinhibition confirmed that CYP3A2 and CYP3A4 were responsible for the hepatic metabolism of TRA 4beta-C hydroxylation. Using RAF, the percent contributions of CYP3A1 and CYP3A2 to 4beta-C hydroxylation of TRA in rat liver microsomes were estimated as 5 to 6 and 94 to 96, respectively, and those of CYP3A4 and CYP3A5 in human liver microsomes as 70 to 72 and 28 to 30%, respectively. These results suggest that CYP3A2 and CYP3A4 are the main form involved in the 4beta-C hydroxylation of TRA in rat and human liver microsomes.
Lin
Yu-Husan
YH
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Peng
Fu-Chuo
FC
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011714:Pyrans / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D007527:Isoenzymes; D008565:Membrane Proteins; D011714:Pyrans; C040403:territrem C; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human