PERIPUBERTAL ANDROGEN IMPRINTING OF RAT HEPATIC CYTOCHROME-P450 2C11 AND STEROID 5-ALPHA-REDUCTASE - PRETRANSLATIONAL REGULATION AND IMPACTON MICROSOMAL DRUG ACTIVATION

To characterize the dose response and time course of peripubertal test osterone imprinting of rat hepatic CYP2C11 and steroid Sa-reductase an d to gain further insights into the mechanism and consequences of peri pubertal androgen imprinting of these enzymes, prepubertally gonadecto mized female rats were injected s.,c. with testosterone enanthate (5 m u mol/kg/day) on days 35 to 49 (peripubertal period) or days 81 to 89 (adulthood) and then sacrificed on day 90. Androgen treatment during t he peripubertal or adult period increased hepatic microsomal testoster one 2 alpha-hydroxylase activity by 4- to 5-fold and decreased steroid 5 alpha-reductase activity by 30 to 50%, By comparison, androgen admi nistration during both periods completely masculinized these two enzym e activities. Whereas shortening the duration of treatment to 5 days d uring the peripubertal and adult periods resulted in only a partial ma sculinization of these activities, reducing the dosage of testosterone enanthate from 5 mu mol/kg/day to 2.5 mu mol/kg/day during both the p eripubertal (15 days) and adult periods (9 days) still fully masculini zed testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase act ivities, Northern blot analysis showed that peripubertal and adult tes tosterone treatment of female rats increased hepatic CYP2C11 mRNA leve ls, decreased steroid 5 alpha-reductase mRNA levels and did not change CYP2C6 mRNA levels. Enhanced cyclophosphamide 4-hydroxylation and ifo sfamide 4-hydroxylation was found in liver microsomes isolated from ad ult female rats exposed to testosterone during puberty and adult life. In contrast to once daily subcutaneous injections, continuous testost erone release via subcutaneous implant was ineffective in producing th e long-term changes in testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase activities. Overall, the present study establishes tha t peripubertal androgen imprinting of CYP2C11 and steroid 5 alpha-redu ctase can be achieved after daily subcutaneous testosterone administra tion. This occurs by a pretranslational mechanism(s), which lead to lo ng-lasting effects on microsomal drug activation.