4-Methylthiobenzoic acid reduces cisplatin nephrotoxicity in rats without compromising anti-tumour activity.
Administration of 4-methylthiobenzoic acid (MTBA) (100 mg/kg) strongly reduced cisplatin nephrotoxicity (7.5 mg/kg, 20 min after MTBA) in rats as determined by histopathology and blood urea nitrogen. Anti-tumour activity against a colonic adenocarcinoma, CC 531, that was implanted in rats, was unaffected by MTBA pretreatment. Studies with isolated renal proximal tubular cells (PTC) demonstrated that preincubation of the cells with MTBA diminished cisplatin nephrotoxicity in vitro as it did in vivo. Preincubation of the PTC with probenecid completely abolished the protective effect of MTBA against cisplatin toxicity. These data indicate that MTBA is actively transported into the PTC. The mechanism of action of MTBA was investigated by NMR studies which showed that cisplatin and cis-diamminediaquaplatinum(II), its hydrolysis product, reacted with the methylthio-sulphur. We suggest that MTBA after selective accumulation in the kidney inactivates cisplatin intracellularly by nucleophilic attack of the methylthio-sulphur to the Pt-moiety. Since MTBA shows no acute toxicity in the rat, even if administered at very high doses, it may be useful to suppress the nephrotoxic side effects of cisplatin anti-tumour therapy.
Division of Toxicology, Leiden University, The Netherlands.
P J
PJ
Boogaard
E L
EL
Lempers
G J
GJ
Mulders
J H
JH
Meerman
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011919:Rats, Inbred Strains; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D013440:Sulfides; C066074:4-(methylthio)benzoic acid; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002945:Cisplatin