Downregulation of Hepatic Carbonyl Reductase Type 1 in End-Stage Renal Disease.
The functional expression of several hepatic drug metabolizing enzymes and transporters are altered in patients with end-stage renal disease (ESRD). We aimed to assess the effect of ESRD on the expression and function of hepatic reductases. Cytosolic and microsomal fractions were isolated from liver tissue from deceased ESRD (n=10) and deceased control patients (n=11). Gene and protein expression, and metabolic activity of reductases were assessed by conducting qRT-PCR, Western blotting and enzyme kinetics, respectively. A 65% decrease in carbonyl reductase 1 protein expression (p<0.05), and a trend toward decreased reductase mRNA expression and activity was observed in ESRD livers versus controls. These results demonstrate a trend toward decreased functional expression of selective hepatic reductases in ESRD livers, which may partially explain altered pharmacokinetics of CBR1 drug substrates in ESRD. Future studies with larger sample size are warranted to confirm these findings.
Osama Y
OY
Alshogran
Bradley L
BL
Urquhart
Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, 208 Salk Pavilion, 335 Sutherland Drive, Pittsburgh, PA, 15261, USA. nolin@pitt.edu.
Thomas D
TD
Nolin
D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D013379:Substrate Specificity; D014859:Warfarin / Q000378:metabolism
D012333:RNA, Messenger; D014859:Warfarin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human