Inhibition of hepatic microsomal drug metabolism by the steroid hydroxylase inhibitor SU-10'603.
SU-10'603 is a pyridine derivative that has been widely used as a steroid 17-hydroxylase inhibitor. Studies were done to compare the effects of SU-10'603 with those of the structurally related compound, metyrapone, on hepatic microsomal drug metabolism in vitro in rats and guinea pigs. In rat liver microsomes, SU-10'603 produced a concentration-dependent (0.01 to 1.0 mM) inhibition of ethylmorphine demethylation, aniline hydroxylation, and benzo[a]pyrene hydroxylation. A concentration of 0.1 to 0.2 mM decreased the metabolism of all three substrates by approximately 50%. SU-10'603 was a more potent inhibitor of ethylmorphine metabolism than metyrapone, and its relative potency was even greater with respect to aniline and benzo[a]pyrene metabolism. Similar results were obtained with guinea pig liver microsomes. SU-10'603 and metyrapone produced type II spectral changes in hepatic microsomes, but the apparent affinity of SU-10'603 for cytochrome(s) P-450 was greater than that of metyrapone. Both compounds inhibited the binding of type I substrates to microsomal cytochromes P-450; SU-10'603 was the more potent inhibitor. The results indicate that SU-10'603 is a potent inhibitor of hepatic microsomal monooxygenases whose mechanism of action is similar to that of metyrapone.
LaCagnin
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West Virginia University Medical Center, Morgantown 26506.
Patricoski
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Colby
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D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000037:antagonists & inhibitors; D005037:Ethylmorphine-N-Demethylase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; C001953:SU 10603; D013250:Steroid Hydroxylases; D000815:Aniline Hydroxylase; D001579:Benzopyrene Hydroxylase; D005037:Ethylmorphine-N-Demethylase; D008797:Metyrapone