Methimazole protection of rats against chemically induced kidney damage in vivo.
Because methimazole has antioxidant properties, the effects of methimazole treatment on cephaloridine, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), 2-bromohydroquinone (2-BHQ) and cis-diaminedichloroplatinum (II) (cisplatin)-induced nephrotoxicity were investigated. Rats given cephaloridine (1 g/kg), cisplatin (5 mg/kg), DCVC (100 mg/kg) or 2-BHQ (157 mg/kg) i.p. exhibited significant elevations in blood urea nitrogen concentrations, which correlated with appearance of distinct renal histopathological changes. Cephaloridine, DCVC or 2-BHQ-induced nephrotoxicity was reduced only when methimazole (20-40 mg/kg) was given 30 min before the nephrotoxicant, whereas cisplatin-induced nephrotoxicity was reduced when methimazole was given 30 min before and up to 4 hr after cisplatin. Because the renal organic acid transport system plays an important role in the nephrotoxicity of cephaloridine, cisplatin and DCVC, the role of the organic acid transport system in the renal uptake of methimazole was investigated. With rat kidney cortical slices, methimazole uptake was time- and concentration-dependent; however, the organic acid transport substrates, probenecid (1 mM) and p-aminohippuric acid (7.5 mM), were ineffective in blocking methimazole uptake. Furthermore, cephaloridine (1 mM) uptake by kidney cortical slices was not affected by methimazole (5 mM). Rats given methimazole (40 mg/kg) 30 min before cephaloridine (2 g/kg) had serum and kidney cephaloridine concentrations similar to rats given cephaloridine only, but the methimazole-pretreated rats were significantly protected against cephaloridine-induced oxidation of renal nonprotein thiols. These results show that methimazole does not inhibit the transport of cephaloridine into the kidneys, but may protect against cephaloridine-induced renal damage by acting as an antioxidant within the kidneys.
Sausen
P J
PJ
Department of Comparative Biosciences, University of Wisconsin, Madison.
Elfarra
A A
AA
Cooley
A J
AJ
D000818:Animals; D001806:Blood Urea Nitrogen; D002509:Cephaloridine / Q000009:adverse effects; D002945:Cisplatin / Q000009:adverse effects; D003545:Cysteine / Q000009:adverse effects / Q000031:analogs & derivatives; D006873:Hydroquinones / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008713:Methimazole / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism
D006873:Hydroquinones; D013438:Sulfhydryl Compounds; D008713:Methimazole; C042377:2-bromohydroquinone; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine; D002509:Cephaloridine; D002945:Cisplatin; D010100:Oxygen