Diazepam metabolism in the kidneys of male and female rats of various strains.
Previously, we have reported drastic strain differences of diazepam metabolism in the livers of a variety of rat strain. In this study, to characterize strain and sex differences of diazepam metabolism in the kidney, renal microsomal diazepam metabolic activities were determined in the Dark Agouti (DA), Sprague-Dawley (SD), Brown Norway (BN) and Wistar (WS) strains of rat. We found that the major pathway of diazepam metabolism in the kidney was diazepam N-demethylation, which is different from that in the liver, 3-hydroxylation. A Dose-course (12.5-200 muM of diazepam) study revealed that the DA and WS male rats had higher diazepam N-demethylation activity than the SD and BN rats. In contrast to the males, a lower activity of diazepam N-demethylation was observed in female BN rats. By Western blot analysis, constitutive protein expressions of cytochrome P450 (CYP) 2C11, which is responsible for diazepam N-demethylation, were detected in the 4 strain in both the male and female rats, and the BN rats had lower expression levels of CYP2C11 protein. However, we did not observe significant differences in the kinetic parameters of diazepam N-demethylation. Our results suggested that there was a strain difference in CYP-dependent diazepam N-demethylation in the rat kidney, which is different from the finding in liver microsomes.
Kim
Hyung-Sub
HS
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Sakai
Noriaki
N
Saito
Konomu
K
Fujita
Shoichi
S
Ishizuka
Mayumi
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D003975:Diazepam / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
D014151:Anti-Anxiety Agents; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D003975:Diazepam