The hepatic and intestinal metabolic activities of P450 in rats with surgery- and drug-induced renal dysfunction.
OBJECTIVE
The hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery- and drug-induced renal dysfunction.


METHODS
Renal failure was induced by five-sixths nephrectomy (NR), bilateral ureter ligation (BUL), the intramuscular injection of glycerol (GL), and the intraperitoneal injection of cisplatin (CDDP). Phenytoin 4-hydroxylation, debrisoquine 4-hydroxylation, and testosterone 6beta-hydroxylation were estimated to evaluate the metabolic activities of cytochrome P450 (CYP) 2C, 2D, and 3A, respectively.


RESULTS
The hepatic CYP3A metabolic activities were decreased by 65.9% and 60.2% in NR and GL rats, respectively. The hepatic CYP2C metabolic activity was decreased by 48.8% in CDDP rats. No alteration in hepatic drug-metabolizing activities was observed in BUL rats. On the other hand, the intestinal CYP3A metabolic activity was weakly increased in GL rats but not significantly altered in NR, CDDP, and BUL rats.


CONCLUSIONS
This study suggested (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver.
Okabe
Hiromi
H
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Hasunuma
Miyako
M
Hashimoto
Yukiya
Y
D000818:Animals; D002945:Cisplatin; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000031:analogs & derivatives* / Q000378:metabolism; D005990:Glycerol; D006900:Hydroxylation; D006915:Hydroxytestosterones / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009392:Nephrectomy; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*
D006915:Hydroxytestosterones; C001419:hydroxyphenytoin; C012359:4-hydroxydebrisoquin; D010672:Phenytoin; C025591:6 beta-hydroxytestosterone; D003577:Cytochrome P-450 Enzyme System; D005990:Glycerol; D002945:Cisplatin; D003647:Debrisoquin