EFFECTS OF VARIOUS CYTOCHROME P-450 INDUCERS ON TESTOSTERONE METABOLISM AND SEVERAL MONOOXYGENASE ACTIVITIES IN SPRAGUEDAWLEY (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 thisenzymatic specificity after treatment with phenobarbital, clofibrate,3-methylcholanthrene and pregnenolone-16-carbonitrile. Thesecompounds are known to induce cytochrome P-450 2B, 4A, 1A and3A1. respectively, in the rat. Induction efficiency was establishedby using the usual enzyme activities specific for these P-450s(pentoxyresorufin, lauric acid, ethoxyresorufin and nifedipineoxidase). Five mono hydroxylated TST metabolites were separatedusing a sensitive HPLC procedure. The hydroxylation of TST wasfound to be significantly different between the lines even inthe uninduced state. The formation of the metabolites of TST,hydroxylated on 2 or 7 or 16 positions and oxidated on carbon17 (4), was found to be significantly increased in SpD ratswhen compared with the HAS-LAS lines (P < 0.0001 in eachcase). When the HAS-LAS lines were compared, the quantity of2 and 16 hydroxylated metabolites was found to be significantlylower in LAS rats (P < 0.05). These differences persisted,although in the opposite direction, after 3-methylcholanthrene(P < 0.01 for both 2 and 16) and phenobarbital induction(P < 0.01 for 2). In conclusion, large differences in TSThydroxylation were found between the SpD and HAS-LAS rats whilemore subtle differences were found between the more closelyrelated HAS-LAS lines especially after phenobarbital and 3-methylcholanthreneadministration as confirmed by our enzyme activity results.The above differences in steroid metabolism between HAS andLAS rats may help to explain their contrasting sensitivitiesto alcohol.