Molecular Mechanisms in Nephrotoxicity
Project no. 21367 · Status: Kapanmış · 2019
Summary
The kidney is one of the most important excretory organs in the body and is responsible for the homeostasis of the body. Thus, any damage to structure and function of the kidney can disrupt the normal functioning and balance of the body and it leads to negative consequences. Paracetamol (acetaminophen); is an analgesic and antipyretic drug and overdose of paracetamol can lead to extensive liver and kidney injury. Although the mechanism of hepatotoxicity is extensively studied, mechanism of nephrotoxicity remains to be clarified. The cysteine s-conjugates of halogenated compounds turn into reactive intermediates and cause damage through cysteine s-conjugate beta-lyases in the kidney. Within the scope in the project, it is thought that cysteine s-conjugate of paracetamol might cause nephrotoxicity by the same pathway. For this purpose, cysteine s-conjugate of paracetamol and S- (1,1,2,2-tetrafluoroethyl)-L-cysteine conjugate as a positive control were incubated separately with rat kidney cytosol and mitochondrial fractions in in vitro conditions and formed the pyruvate during the reaction was derivatized and analyzed in HPLC fluorescent detector. When the data is evaluated statistically, paracetamol-cysteine may be a substrate for both the mitochondrial and cytosolic cysteine s-conjugate beta-lyases. On the other hand, the cysteine s-conjugate beta-lyases showed more activity in both fractions with S-(1,1,2,2-tetrafluoroethyl)-L-cysteine compared to paracetamol cysteine as expected. It is not known which cysteine s-conjugate beta-lyase(s) in the cytosol and mitochondria react with paracetamol-cysteine, and whether the thiol compound is reactive. Further studies on the specific enzyme incubations and the elucidation of possible metabolites will provide better insight into the mechanism of nephrotoxicity caused by paracetamol.