Down-regulation of hepatic CYP3A in chronic renal insufficiency.
OBJECTIVE
The objective of this study was to investigate the mechanisms underlying the decrease in hepatic clearance of some drugs metabolized by CYP450 enzymes in chronic renal insufficiency (CRI).


METHODS
CRI was induced in male Sprague-Dawley rats (n = 7) by the remnant kidney model (RKM); control animals (C) (n = 12) underwent sham surgery, of which n = 6 rats were pair-fed (CPF) with CRI rats and others (n = 6) had free access to food. Serum creatinine (Scr) and urea nitrogen (SUN) were monitored every 2 weeks. On day 36, livers were isolated, and microsomes were prepared. Catalytic activities were measured through O-demethylation (CYP2D) and N-demethylation of dextromethorphan (CYP3A) and O-deethylation of 7-ethoxyresorufin (CYP1A2). CYP450 protein and mRNA levels were also measured.


RESULTS
Compared with CPF, Scr and SUN levels in CRI rats were increased twofold (p < 0.01) and 2.5-fold (p < 0.01), respectively. No effect on CYP1A2 and CYP2D activities, mRNA, or protein levels was observed between the groups. There was a reduction (41.8 +/- 20%, p < 0.01) in CYP3A activity, mRNA (p < 0.05), and protein levels (p < 0.05) in CRI rats compared to CPF.


CONCLUSIONS
CRI induced by RKM does not have an effect on hepatic CYP1A2 and CYP2D enzymes but does reduce CYP3A activity, probably through down-regulation of CYP3A2.
Rege
Bhaskar
B
Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Krieg
Richard
R
Gao
Ning
N
Sarkar
Mohamadi A
MA
D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism; D015153:Blotting, Western; D002384:Catalysis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D015536:Down-Regulation; D007527:Isoenzymes / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating