Peripubertal androgen imprinting of rat hepatic cytochrome P450 2C11 and steroid 5 alpha-reductase: pretranslational regulation and impact on microsomal drug activation.
To characterize the dose response and time course of peripubertal testosterone imprinting of rat hepatic CYP2C11 and steroid 5 alpha-reductase and to gain further insights into the mechanism and consequences of peripubertal androgen imprinting of these enzymes, prepubertally gonadectomized female rats were injected s.c. with testosterone enanthate (5 mumol/kg/day) on days 35 to 49 (peripubertal period) or days 81 to 89 (adulthood) and then sacrificed on day 90. Androgen treatment during the peripubertal or adult period increased hepatic microsomal testosterone 2 alpha-hydroxylase activity by 4- to 5-fold and decreased steroid 5 alpha-reductase activity by 30 to 50%. By comparison, androgen administration during both periods completely masculinized these two enzyme activities. Whereas shortening the duration of treatment to 5 days during the peripubertal and adult periods resulted in only a partial masculinization of these activities, reducing the dosage of testosterone enanthate from 5 mumol/kg/day to 2.5 mumol/kg/day during both the peripubertal (15 days) and adult periods (9 days) still fully masculinized testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase activities. Northern blot analysis showed that peripubertal and adult testosterone treatment of female rats increased hepatic CYP2C11 mRNA levels, decreased steroid 5 alpha-reductase mRNA levels and did not change CYP2C6 mRNA levels. Enhanced cyclophosphamide 4-hydroxylation and ifosfamide 4-hydroxylation was found in liver microsomes isolated from adult female rats exposed to testosterone during puberty and adult life. In contrast to once daily subcutaneous injections, continuous testosterone release via subcutaneous implant was ineffective in producing the long-term changes in testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase activities. Overall, the present study establishes that peripubertal androgen imprinting of CYP2C11 and steroid 5 alpha-reductase can be achieved after daily subcutaneous testosterone administration. This occurs by a pretranslational mechanism(s), which lead to long-lasting effects on microsomal drug activation.
Chang
T K
TK
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Bellward
G D
GD
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000187:drug effects; D003520:Cyclophosphamide / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D007069:Ifosfamide / Q000378:metabolism; D007173:Imprinting, Psychological; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*
D004343:Drug Implants; D012333:RNA, Messenger; D013739:Testosterone; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D009251:NADPH-Ferrihemoprotein Reductase; D007069:Ifosfamide