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)
Duffy
O
O
Laboratoire de Biochimie-Nutrition, Equipe d'accueil DRED, Faculté de Médecine, Brest, France.
Berthou
F
F
Bardou
L G
LG
Ménez
J F
JF
D000437:Alcoholism / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D006900:Hydroxylation; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D010105:Oxygenases / Q000096:biosynthesis*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases