Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids.
We have recently shown that carnitine deficiency could represent a risk factor in paracetamol hepatotoxicity. By the same token, d-carnitine-induced carnitine deficiency aggravated carboplatin nephropathy following challenge with a single dose (35mg/kg, IP) of the platinum drug in male Swiss albino rats. The combination modality induced marked degenerative changes and severe inflammation in kidney tissues that surpassed either carboplatin or d-carnitine given alone. The combined regimen synergistically increased the serum levels of creatinine, blood urea nitrogen (BUN), tumor necrosis factor alpha (TNF-alpha), palmitate, and kidney malondialdehyde (MDA), adenosine triphosphate (ATP), nitric oxide (NO) contents as well as kidney myeloperoxidase (MPO) activity. The only parameter that has been notably decreased was the kidney reduced glutathione (GSH) level. Exaggeration by carnitine deficit of the deleterious effects of carboplatin is most probably ascribed to energy starvation. The reduction in kidney content of ATP parcels was associated with elevation of serum palmitate level that reflected debilitated fatty acid oxidation, and this further deteriorated energy resources in kidney tissues. Compromising the oxidant/anti-oxidant balance and modulating the release of some inflammatory endocoids namely, TNF-alpha and NO could also possibly account for such combinatorial detrimental toxicity. The current study was further extended to elucidate any possible nephroprotective effects of l-carnitine. Interestingly, carnitine supplementation ahead of carboplatin challenge ameliorated and almost normalized all the biochemical parameters and also mitigated the injurious effects of the cytotoxic drug. Thus, one could conclude that carnitine deficiency, whether being a causative clue or a sequela, might represent a risk factor in carboplatin nephropathy.
Department of Pharmacol & Toxicol, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt. hmmarafa@yahoo.com
Hossam M M
HM
Arafa
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001806:Blood Urea Nitrogen; D016190:Carboplatin / Q000633:toxicity*; D002331:Carnitine / Q000172:deficiency*; D003404:Creatinine / Q000097:blood; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D003404:Creatinine; D016190:Carboplatin; D002331:Carnitine