Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats.
This study investigates whether or not carnitine deficiency is a risk factor and could contribute to cisplatin-induced liver toxicity. A total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, propionyl-l-carnitine (500 mg/kg), and d-carnitine (500 mg/kg), respectively, for 10 successive days. The fourth, fifth and sixth groups were injected intraperitoneally with the same doses of normal saline, propionyl-l-carnitine and d-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Administration of the standard nephrotoxic dose of cisplatin did not produce any changes in serum alanine transaminase and gamma-glutamyl transferase and no morphological changes in liver tissues. However, it did produce a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione content in liver tissues. On the other hand, combined treatment with cisplatin and d-carnitine induced a dramatic increase in serum alanine transaminase and gamma-glutamyl transferase, as well as progressive reduction in total carnitine and ATP content in liver tissue. Moreover, histopathological examination of liver tissues confirmed the biochemical data, where cisplatin and d-carnitine combination showed signs of liver injury manifested as focal necro-inflammatory changes and portal inflammation. Interestingly, in carnitine supplemented rats using propionyl-l-carnitine, cisplatin did not produce any biochemical and histopathological changes in liver tissues. In conclusion, data from this study suggest for the first time that (1) carnitine deficiency is a risk factor and could precipitate cisplatin-induced hepatotoxicity, (2) oxidative stress is not the main cause of cisplatin-related hepatotoxicity and (3) propionyl-l-carnitine prevents the development of cisplatin-induced liver injury.
Al-Majed
Abdulhakeem A
AA
Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. majed107@hotmail.com
D000255:Adenosine Triphosphate; D000410:Alanine Transaminase / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D002331:Carnitine / Q000031:analogs & derivatives / Q000172:deficiency* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D005978:Glutathione / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D009566:Nitrates; D009573:Nitrites; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D017392:Thiobarbituric Acid Reactive Substances; D014804:Vitamin B Deficiency; D005723:gamma-Glutamyltransferase / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D009566:Nitrates; D009573:Nitrites; D017392:Thiobarbituric Acid Reactive Substances; C003223:propionylcarnitine; D000255:Adenosine Triphosphate; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D005978:Glutathione; D002945:Cisplatin; D002331:Carnitine