Cysteine conjugates of acetaminophen and p-aminophenol are potent inducers of cellular impairment in human proximal tubular kidney HK-2 cells.

Autor: Rousar T; Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic. Tomas.Rousar@upce.cz., Handl J; Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Capek J; Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Nyvltova P; Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Rousarova E; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Kubat M; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Smid L; Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Vanova J; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic., Malinak D; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic., Musilek K; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic., Cesla P; Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 532 10, Pardubice, Czech Republic.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2023 Nov; Vol. 97 (11), pp. 2943-2954. Date of Electronic Publication: 2023 Aug 28.
DOI: 10.1007/s00204-023-03569-2
Abstrakt: Acetaminophen (APAP) belong among the most used analgesics and antipyretics. It is structurally derived from p-aminophenol (PAP), a potent inducer of kidney toxicity. Both compounds can be metabolized to oxidation products and conjugated with glutathione. The glutathione-conjugates can be cleaved to provide cysteine conjugates considered as generally nontoxic. The aim of the present report was to synthesize and to purify both APAP- and PAP-cysteine conjugates and, as the first study at all, to evaluate their biological effects in human kidney HK-2 cells in comparison to parent compounds. HK-2 cells were treated with tested compounds (0-1000 µM) for up to 24 h. Cell viability, glutathione levels, ROS production and mitochondrial function were determined. After 24 h, we found that both APAP- and PAP-cysteine conjugates (1 mM) were capable to induce harmful cellular damage observed as a decrease of glutathione levels to 10% and 0%, respectively, compared to control cells. In addition, we detected the disappearance of mitochondrial membrane potential in these cells. In the case of PAP-cysteine, the extent of cellular impairment was comparable to that induced by PAP at similar doses. On the other hand, 1 mM APAP-cysteine induced even larger damage of HK-2 cells compared to 1 mM APAP after 6 or 24 h. We conclude that cysteine conjugates with aminophenol are potent inducers of oxidative stress causing significant injury in kidney cells. Thus, the harmful effects cysteine-aminophenolic conjugates ought to be considered in the description of APAP or PAP toxicity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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