cis-Diamminedichloroplatinum induces peroxisomes as well as CYP4A1 in rat kidney.
Effects of cis-diamminedichloroplatinum (cisplatin) on rat kidney were investigated. Clinical parameters in rat urine and blood were studied. Blood urea nitrogen (BUN) and creatinine in blood and K+ in urine increased, but Na+ in urine decreased. Contents of total P450 and metabolic activities towards lauric acid and arachidonic acid in rat renal microsomes were not changed by cisplatin treatment. The levels of P450 isozymes (CYP4A1, 4A2, 4A8 and 2C23) were determined in rat renal microsomes by immunoblotting. The levels of CYP4A2 and 4A8 which are lauric acid omega-hydroxylases were not changed, but the levels of CYP2C23 and 4A1 were increased significantly by cisplatin treatment. Effects of clofibrate, a typical inducer for CYP4A1, on rat kidney were compared with those of cisplatin. Clofibrate induced palmitoyl CoA oxidase (a marker enzyme of peroxysome), CYP4A1, and CYP4A2 and reduced triglyceride level in plasma. Cisplatin had similar effects to clofibrate and induced peroxysomes as well as CYP4A1, although the effects were at a lesser extent than those of clofibrate. The induction levels of CYP4A1 correlated with increased levels of BUN. The present findings suggest that induction of P450 by cisplatin may take part in the renal injury or nephrotoxicity of cisplatin.
Nakamura
M
M
Laboratory of Chemistry, Osaka City University Medical School, Japan.
Imaoka
S
S
Tanaka
E
E
Misawa
S
S
Funae
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D002994:Clofibrate / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D015151:Immunoblotting; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D007677:Kidney Function Tests; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
D000970:Antineoplastic Agents; C000717351:Cyp2c23 protein, rat; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; C028427:palmitoyl CoA oxidase; D002994:Clofibrate; D002945:Cisplatin