Abstract
We have isolated a hamster liver cDNA whose expression is induced upon feeding hamsters with a cholic acid-rich diet. It was identified as a cytochrome P450 family 3 protein, by sequence homology, and named CYP3A10. The activity of CYP3A10 was determined by transient expression of its cDNA in transfected COS cells and was found to hydroxylate lithocholic acid at position 6 beta. CYP3A10 RNA is 50-fold higher in males than in female hamsters. In males, it appears to be regulated by age with expression highest after puberty. Shortly after weaning (28 days), cholic acid feeding of male hamsters elevates the level of message over that of hamsters fed with normal laboratory chow. Females do not exhibit regulation by cholic acid. In hamster liver, murideoxycholic acid, the 6 beta-metabolite of lithocholic acid, is the major hydroxylated product of lithocholic acid. Lithocholic acid 6 beta-hydroxylase (6 beta-hydroxylase) activity is greatly diminished in hamster female liver microsomes as would be expected due to the lack of CYP3A10 mRNA in females. Additionally, male liver microsomal 6 beta-hydroxylase activity was increased by cholic acid feeding, consistent with the cholic acid-mediated induction of its RNA. These results indicate that, in male hamsters, 6 beta-hydroxylation is the major pathway for detoxification of lithocholate and that, likely, CYP3A10 is responsible for that activity.
Highlights
We have isolated a hamster liver cDNA whose expression is inducedupon feeding hamsters with a cholic acid-rich diet
Hydroxylase (68-hydroxylase)activity is greatly dihemeproteins that catalyze the oxidation of a variety of endogenous and exogenous substrates in concert with NADPH andNADPH-dependent cytochrome P450 reductase (P450 reductase) (Gonzalez, 1989; Nebert et al, 1991).Many P450s are involved in very different metabolic pathways such as steroid hormone metabolism (Gonzalez, 1989; Nebert et al, 1991), drug detoxification (Guengerich, 1987; Shaw et al, 1989;Shimada andGuengerich, 1985),and bile acidsynthesis (Bjorkhem, 1985; Bjorkhem and Danielsson, 1974) and are regulated by poorly understood molecular mechanisms that induce or suppress expression or activity
That degrade cholesterol absorbed from the diet, it must be eliminated via the bile acid metabolic pathway (Dietschy, 1984)
Summary
From theDepartment of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655. We have isolated a hamster liver cDNA whose expression is inducedupon feeding hamsters with a cholic acid-rich diet. Male liver microsomal 6 B - h ~ - the body (see Fig. 1).Since mammals do not possess enzymes droxylase activity was increased by cholic acid feeding, consistent with the cholic acid-mediatedinduction of its RNA. These results indicate that, in male hamsters, 68-hydroxylation is the major pathway for detoxification of lithocholate and that, likely, CYP3A10 i s responsible for that activity. It is known that 80-90% of intravenously injected cholesterol is catabolized to bile acids (Bjorkhem, 1985).Atherosclerosis, gallstone disease, and some lipid storage diseases may beaffected by the rateof cholesterol elimination via bile acid biosynthesis and excretion (Bjorkhem, 1985)
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