The microsomal monooxygenase system of regenerating liver. An examination of the role of estradiol in the demasculinization of drug metabolism produced by 2/3 partial hepatectomy.
Declines in total cytochrome P450 content and in monooxygenase activities associated with some male specific isozymes of cytochrome P450 have been reported in the rat following 2/3 partial hepatectomy (2/3 PH). In the present study, we examined the effects of 2/3 PH on hepatic microsomal monooxygenase activities towards testosterone, the alkoxyresorufins, p-nitrophenol and carbon tetrachloride in male rats. Levels of P450 apoproteins were determined by Western blot analysis. The effects of hepatectomy and sham operations on plasma growth hormone (GH) pulse profiles and the effects of a single acute dose of estradiol (E2) were studied to determine the role of these factors in 2/3 PH mediated changes in oxidative metabolism. 2/3 PH produced substantial decreases in testosterone hydroxylation at positions 16 alpha, 2 alpha and 7 alpha, but only a small decrease in hydroxylation at position 6 beta. Reductions in CYP 2C11 (P450h) and CYP 2A1 (P450a) expression were observed with Western blot analysis down to 19 and 41% of control values, respectively, but insignificant effects were observed on expression of CYP 3A (P450p family) proteins recognized by a polyclonal antibody raised against rat CYP 3A2 (P450pcn2). In contrast, acute E2 treatment caused a 2-fold increase in expression of CYP 2A1 apoprotein and significantly decreased expression of CYP 2E1 (P450j) apoprotein and dependent monooxygenase activities, but had no significant effect on expression of CYP 2C11. Both sham operations and 2/3 PH caused a temporary decrease in plasma GH concentrations, but secretion returned towards normal 24-48 hr after both operations. These data suggest that some factor other than GH or E2 must be involved in the selective suppression of some P450 isozymes observed after 2/3 PH.
Ronis
M J
MJ
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock 72205.
Lumpkin
C K
CK
Thomas
P E
PE
Ingelman-Sundberg
M
M
Badger
T M
TM
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D013006:Growth Hormone / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D007527:Isoenzymes / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism
D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D013739:Testosterone; D004958:Estradiol; D013006:Growth Hormone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase