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 investigates the effects of diet, age, and strain on rat testicular CYP2A1 expression and assesses the potential role of testicular CYP2A1 in the metabolic activation of carcinogens. In ad libitum-fed 18-week-old Fischer 344 rats, testicular CYP2A1 immunoreactive protein and testosterone 7alpha-hydroxylase activity (7alpha-TOHase) exhibited a circadian variation with a daytime maximum and a night-time minimum (82.2 +/- 42.0 and 21.9 +/- 4.5 pmol 7alpha-hydroxytestosterone/min/mg protein, respectively). Caloric restriction (to 60% of ad libitum consumption), which reduces the severity of Leydig cell tumors in rats, decreased expression of both CYP2A1 and testicular 7alpha-TOHase >80% and eliminated their circadian variation. Conversely, caloric restriction induced a circadian rhythm in testicular 7-benzyloxyresorufin-O-dealkylase activity. Testicular microsomes from ad libitum-fed rats having peak diurnal 7alpha-TOHase activity had significantly greater (30%) microsome-mediated aflatoxin B1-DNA binding activity compared to microsomes prepared from nocturnal phase ad libitum-fed or calorically restricted rats which expressed low 7alpha-TOHase activity. In 12-month-old Fischer 344 rats, high CYP2A1 expression was correlated with severe Leydig cell hyperplasia (r = 0.80), whereas CYP2A immunoreactive protein and 7alpha-TOHase were expressed at lower levels in Sprague-Dawley than in Fischer 344 rats and were undetectable in pig, monkey, and human testes. These are strains/species that do not exhibit significant Leydig cell hyperplasia. This suggests that caloric intake, strain, and circadian factors may all mediate testicular CYP2A1 expression in the rat and that CYP2A1 may in turn influence carcinogen activation and pathological status in the testis.