Distinct forms of cytochrome P-450 are responsible for 6 beta-hydroxylation of bile acids and of neutral steroids.
Cytochrome P-450-dependent 6 beta-hydroxylation of bile acids in rat liver contributes to the synthesis of the quantitatively important pool of 6-hydroxylated bile acids, as well as to the detoxification of hydrophobic bile acids. The lithocholic acid 6 beta-hydroxylation reaction was investigated and compared with androstenedione 6 beta-hydroxylation. Differential responses of these two activities to inducers and inhibitors of microsomal P-450 enzymes, lack of mutual inhibition by the two substrates and differential inhibition by antibodies raised against several purified hepatic cytochromes P-450 were observed. From these results it was concluded that 6 beta-hydroxylation of lithocholic acid is catalysed by P-450 form(s) different from the subfamily IIIA cytochromes P-450 which are responsible for the bulk of microsomal androstenedione 6 beta-hydroxylation. Similar, but more tentative, results revealed that the 7 alpha-hydroxylation of lithocholic acid and of androstenedione may be also catalysed by distinct P-450 enzymes. The results indicate that cytochromes P-450 hydroxylating bile acids are distinct from analogous enzymes that carry out reactions of the same regio- and stereo-specificity on neutral steroids (steroid hormones). A comparison of pairs of cytochromes P-450 that catalyse the same reaction on closely related steroid molecules will help to define those structural elements in the proteins that determine the recognition of their respective substrates.
Zimniak
P
P
Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock 72205.
Holsztynska
E J
EJ
Radominska
A
A
Iscan
M
M
Lester
R
R
Waxman
D J
DJ
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006900:Hydroxylation; D008095:Lithocholic Acid / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
D001647:Bile Acids and Salts; D065607:Cytochrome P-450 Enzyme Inhibitors; D013256:Steroids; D000735:Androstenedione; D008095:Lithocholic Acid; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D002994:Clofibrate; D010634:Phenobarbital