Effects of various cytochrome P-450 inducers on testosterone metabolism and several monooxygenase activities in Sprague-Dawley (SpD), high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats.

Hydroxylation of testosterone (TST) has been shown to be regio- and stereo-specific for a number of cytochrome P-450 isoenzymes. Three rat lines [Sprague-Dawley (SpD), high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS)] were tested for this enzymatic specificity after treatment with phenobarbital, clofibrate, 3-methylcholanthrene and pregnenolone-16 alpha-carbonitrile. These compounds are known to induce cytochrome P-450 2B, 4A, 1A and 3A1, respectively, in the rat. Induction efficiency was established by using the usual enzyme activities specific for these P-450s (pentoxyresorufin, lauric acid, ethoxyresorufin and nifedipine oxidase). Five mono hydroxylated TST metabolites were separated using a sensitive HPLC procedure. The hydroxylation of TST was found to be significantly different between the lines even in the uninduced state. The formation of the metabolites of TST, hydroxylated on 2 alpha or 7 alpha or 16 alpha positions and oxidated on carbon 17 (delta 4), was found to be significantly increased in SpD rats when compared with the HAS-LAS lines (P < 0.0001 in each case). When the HAS-LAS lines were compared, the quantity of 2 alpha and 16 alpha hydroxylated metabolites was found to be significantly lower in LAS rats (P < 0.05). These differences persisted, although in the opposite direction, after 3-methylcholanthrene (P < 0.01 for both 2 alpha and 16 alpha) and phenobarbital induction (P < 0.01 for 2 alpha).(ABSTRACT TRUNCATED AT 250 WORDS)