EFFECTS OF CALORIC RESTRICTION ON EXPRESSION OF TESTICULAR CYTOCHROME-P450 ENZYMES ASSOCIATED WITH THE METABOLIC-ACTIVATION OF CARCINOGENS

Previous work demonstrated that microsomal cytochrome P4502A1 (CYP2A1) is expressed in rat testicular Leydig cells. The present study invest igates the effects of diet, age, and strain on rat testicular CYP2A1 e xpression and assesses the potential role of testicular CYP2A1 in the metabolic activation of carcinogens. In ad libitum-fed 18-week-old Fis cher 344 rats, testicular CYP2A1 immunoreactive protein and testostero ne 7 alpha-hydroxylase activity (7 alpha-TOHase) exhibited a circadian variation with a daytime maximum and a night-time minimum (82.2 +/- 4 2.0 and 21.9 +/- 4.5 pmol 7 alpha-hydroxytestosterone/min/mg protein, respectively). Caloric restriction (to 60% of ad libitum consumption), which reduces the severity of Leydig cell tumors in rats, decreased e xpression of both CYP2A1 and testicular 7 alpha-TOHase >80% and elimin ated their circadian variation. Conversely, caloric restriction induce d a circadian rhythm in testicular 7-benzyloxyresorufin-O-dealkylase a ctivity. Testicular microsomes from ad libitum-fed rats having peak di urnal 7 alpha-TOHase activity had significantly greater (30%) microsom e-mediated aflatoxin B-1-DNA binding activity compared to microsomes p repared from nocturnal phase ad libitum-fed or calorically restricted rats which expressed low 7 alpha-TOHase activity. In 12-month-old Fisc her 344 rats, high CYP2A1 expression was correlated with severe Leydig cell hyperplasia (r = 0.80), whereas CYP2A immunoreactive protein and 7 alpha-TOHase were expressed at lower levels in Sprague-Dawley than in Fischer 344 rats and were undetectable in pig, monkey, and human te stes. These are strains/species that do not exhibit significant Leydig cell hyperplasia. This suggests that caloric intake, strain, and circ adian factors may all mediate testicular CYP2A1 expression in the rat and that CYP2A1 may in turn influence carcinogen activation and pathol ogical status in the testis.