Investigation of paracetamol-induced renal toxicity mechanism at cell, organ and organism level
Project no. 22922 · Status: Kapanmış · 2021
Summary
<p>Paracetamol (PAR) is considered the safest and most used analgesic-antipyretic drug even in pregnancy. However, it causes acute liver damage and kidney toxicity in case of overdose, which can be fatal. Although the mechanism of hepatotoxicity is well defined, it remained unclear how nephrotoxicity develops. It has been demonstrated by us in a collaboration with international colleagues that the mechanism of paracetamol-induced kidney toxicity is completely different than the hepatotoxicity at the molecular level. In this project we aimed to understand the toxicity of PAR-induced kidney damage by a series of <em>in vitro</em> and <em>in vivo </em>approaches, and our two hypotheses were tested. The findings we obtained showed that, in accordance with our hypotheses that the toxic metabolite of PAR, namely PAR-Cys is a substrate for the enzyme <em>Cysteine conjugate β-lyase. </em>In addition, it has been observed that there is mitochondrial damage in the target kidney proximal tubule cells upon PAR-Cys exposure such as changes in expression levels of electron transport chain proteins and in activities of chain complexes, and induction of mitochondrial permeability transition pores. Diminishing of mitotoxicity in PAR-administered mice by MitoTempo, which is a mitochondria-specific antioxidant, significantly support these observations. The findings we obtained proved once again that the mechanism of PAR-induced nephrotoxicity is completely different than liver damage. Also, various mitochondrial and cellular parameters were analyzed for the first time and their role in the mechanism of kidney toxicity was determined. </p>