A specific loss of growth hormone abolished sex-dependent expression of hepatic cytochrome P450 in dwarf rats: reversal of the profiles by growth hormone-treatment.
A spontaneous dwarf rat derived from a colony of Sprague-Dawley (SD) strain has no detectable level of growth hormone (GH) in pituitary, although it contained other hormones like prolactin and ACTH. Hepatic profile of cytochrome P450 (P450) differed clearly between dwarf and normal SD rats. A male-specific form of P450, CYP2C11, was detected in dwarf male rat livers, while the level was one-third of the normal SD livers. This P450 was also detected in dwarf females. Other male-specific CYP3A2 and CYP3A18 were also contained in both sexes of dwarf rats, whereas a female-specific form, CYP2C12, was not detectable in dwarf females. Phenobarbital-inducible CYP2B1 and CYP2B2 were constitutively expressed in dwarf rats, although substantially absent in normal SD rats. To assess the role of GH on hepatic P450 expression, GH was given to dwarf rats for 7 to 9 days. The intermittent injection (mimicking the male secretory pattern) resulted in the elevation of CYP2C11 to a level as observed in normal SD males. Continuous infusion of GH (mimicking the female secretory pattern) evoked CYP2C12 in livers of both sexes of dwarf rats, whereas the treatment decreased levels of CYP3A2, CYP3A18, and CYP2B1. These results clearly demonstrate that specific defect of GH, but not pituitary, cause the clear changes in hepatic P450 forms including sex-specific forms. The present study provides evidence further to strengthen the principal role of GH on the regulation of expression of P450 in rat livers.
Shimada
M
M
Division of Drug Metabolism and Molecular Toxicology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Murayama
N
N
Nagata
K
K
Hashimoto
H
H
Ishikawa
H
H
Yamazoe
Y
Y
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism; D004392:Dwarfism / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D013006:Growth Hormone / Q000172:deficiency* / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000378:metabolism
D007527:Isoenzymes; D012333:RNA, Messenger; D013006:Growth Hormone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster; D009251:NADPH-Ferrihemoprotein Reductase