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It is structurally derived from <jats:italic>p<\/jats:italic>-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\u00a0conjugates 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\u20131000\u00a0\u00b5M) for up to 24\u00a0h. Cell viability, glutathione levels, ROS production and mitochondrial function were determined. After 24\u00a0h, we found that both APAP- and PAP-cysteine conjugates (1\u00a0mM) 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\u00a0mM APAP-cysteine induced even larger damage of HK-2 cells compared to 1\u00a0mM APAP after 6 or 24\u00a0h. 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.<\/jats:p>","DOI":"10.1007\/s00204-023-03569-2","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T13:04:05Z","timestamp":1693227845000},"page":"2943-2954","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cysteine conjugates of acetaminophen and p-aminophenol are potent inducers of cellular impairment in human proximal tubular kidney HK-2 cells"],"prefix":"10.1007","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6893-821X","authenticated-orcid":false,"given":"Tomas","family":"Rousar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-2825","authenticated-orcid":false,"given":"Jiri","family":"Handl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3713-2467","authenticated-orcid":false,"given":"Jan","family":"Capek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-6407","authenticated-orcid":false,"given":"Pavlina","family":"Nyvltova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7552-814X","authenticated-orcid":false,"given":"Erika","family":"Rousarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4841-087X","authenticated-orcid":false,"given":"Miroslav","family":"Kubat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-9458","authenticated-orcid":false,"given":"Lenka","family":"Smid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5780-243X","authenticated-orcid":false,"given":"Jana","family":"Vanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0665-0667","authenticated-orcid":false,"given":"David","family":"Malinak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7504-4062","authenticated-orcid":false,"given":"Kamil","family":"Musilek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-0487","authenticated-orcid":false,"given":"Petr","family":"Cesla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"key":"3569_CR1","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1146\/annurev.pharmtox.38.1.501","volume":"38","author":"MW Anders","year":"1998","unstructured":"Anders MW, Dekant W (1998) Glutathione-dependent bioactivation of haloalkenes. 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