Effect of exogenous growth hormone on somatic growth, gonadal development, and hepatic CYP2C11 and CYP2C12 expression in prepubertal intact male rats.
The influence of exogenous growth hormone (GH) on pubertal maturation, as assessed by growth, age of preputial separation, testicular development, and hepatic expression of sexually dimorphic cytochrome P450 (CYP) enzymes, was investigated. Treatment of 22-day old prepubertal intact male rats with twice daily subcutaneous (s.c.) injections of rat recombinant GH (0.12 microg/g body weight) for 12 or 21 days did not affect body weight, skeletal growth, or testicular weight. By comparison, GH suppressed hepatic CYP2C1 enzyme activity, protein, and mRNA levels but induced CYP2C12 expression. GH suppressed CYP2C11 expression by approximately 60% in prepubertal rats as compared with 30% in adult rats, whereas it increased CYP2C12 levels to 80% of the normal female levels but had no effect in adult male rats. Twice daily intravenous injections of GH suppressed CYP2C11 only. Increasing the s.c. dose of GH 30-fold produced little or no additional change in CYP2C11 or CYP2C12 expression, whereas it modestly in creased body weight and skeletal growth and reduced testicular weight. Overall, the present study provides the first demonstration that prepubertal administration (22-33 days of age) of GH at a pharmacologically relevant dose (0.12 microg/g twice daily) suppressed hepatic expression of CYP2C11 in 34-day-old intact male rats, suggesting that in this age group the liver is intrinsically responsive to transcription factors involved in the regulation of GH-dependent, sex-specific CYP gene expression. A higher dose (3.6 microg/g) of GH administered during the prepubertal period was required to elicit a modest effect on somatic growth and gonadal development.
Kawai
M
M
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Bandiera
S M
SM
Chang
T K
TK
Bellward
G D
GD
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000187:drug effects* / Q000502:physiology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
D012333:RNA, Messenger; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C034694:steroid 15-beta-hydroxylase