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 st ereo-specific for a number of cytochrome P-450 isoenzymes. Three rat l ines [Sprague-Dawley (SpD), high alcohol sensitivity (HAS) and low alc ohol sensitivity (LAS)] were tested for this enzymatic specificity aft er treatment with phenobarbital, clofibrate, 3-methylcholanthrene and pregnenolone-16 alpha-carbonitrile. These compounds are known to induc e cytochrome P-450 2B, 4A, 1A and 3A1, respectively, in the rat. Induc tion efficiency was established by using the usual enzyme activities s pecific for these P-450s (pentoxyresorufin, lauric acid, ethoxyresoruf in and nifedipine oxidase). Five mono hydroxylated TST metabolites wer e 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, hydroxylate d 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 H AS-LAS lines were compared, the quantity of 2 alpha and 16 alpha! hydr oxylated metabolites was found to be significantly lower in LAS rats ( P < 0.05). These differences persisted, although in the opposite direc tion, after 3-methylcholanthrene (P < 0.01 for both 2 alpha( and 16 al pha) and phenobarbital induction (P < 0.01 for 2 alpha). In conclusion , large differences in TST hydroxylation were found between the SpD an d HAS-LAS rats while more subtle differences were found between the mo re closely related HAS-LAS lines especially after phenobarbital and 3- methylcholanthrene administration as Confirmed by our enzyme activity results. The above differences in steroid metabolism between HAS and L AS rats may help to explain their contrasting sensitivities to alcohol .