Cresol isomers: comparison of toxic potency in rat liver slices
- PMID: 8128495
- DOI: 10.1006/taap.1994.1048
Cresol isomers: comparison of toxic potency in rat liver slices
Abstract
A comparison of the toxicity of cresol isomers (o-, m-, and p-methylphenol) was carried out using precision-cut rat liver slices as a test system. At equimolar concentrations p-cresol was the most toxic isomer. A 5- to 10-fold higher concentration of either the o- or m-isomers was required to observe the same degree of cell killing as p-cresol. The toxicity of p-cresol was inhibited by the thiol precursor N-acetylcysteine and was enhanced by pretreatment of liver slices with diethyl maleate to deplete glutathione. These treatments, however, had little effect on either o- or m-cresol toxicity. p-Cresol rapidly depleted intracellular glutathione levels, while the o- and m-isomers depleted glutathione to a lesser extent. [14C]p-cresol was metabolized to a reactive intermediate which covalently bound to slice protein and was inhibited by N-acetylcysteine. In microsomal incubations covalent binding of [14C]p-cresol metabolites was also observed. This binding was inhibited by glutathione and resulted in the formation of a glutathione conjugate. In the absence of glutathione, p-hydroxybenzyl alcohol was the major microsomal metabolite formed from p-cresol, but this compound was not toxic to liver slices at a concentration of 2 mM. These results demonstrate that p-cresol is the most toxic cresol isomer in rat liver tissue and that its toxicity is dependent on the formation of a reactive intermediate. The results also suggest that the mechanism(s) of toxicity of the o- and m-isomers may differ from that of p-cresol.
Similar articles
-
Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity.Chem Res Toxicol. 1995 Jan-Feb;8(1):55-60. doi: 10.1021/tx00043a007. Chem Res Toxicol. 1995. PMID: 7703367
-
Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices.Drug Metab Dispos. 1990 Nov-Dec;18(6):929-36. Drug Metab Dispos. 1990. PMID: 1981539
-
Studies on the mechanism of hepatotoxicity of 4-methylphenol (p-cresol): effects of deuterium labeling and ring substitution.Chem Biol Interact. 1996 Jun;101(1):1-11. doi: 10.1016/0009-2797(96)03707-6. Chem Biol Interact. 1996. PMID: 8665615
-
Bioactivation of 4-methylphenol (p-cresol) via cytochrome P450-mediated aromatic oxidation in human liver microsomes.Drug Metab Dispos. 2005 Dec;33(12):1867-76. doi: 10.1124/dmd.105.006387. Epub 2005 Sep 20. Drug Metab Dispos. 2005. PMID: 16174805
-
Molecular structure and hepatotoxicity: compared data about two closely related thiophene compounds.J Hepatol. 1997;26 Suppl 2:22-5. doi: 10.1016/s0168-8278(97)80493-x. J Hepatol. 1997. PMID: 9204406 Review.
Cited by
-
The microbial metabolite p-cresol compromises the vascular barrier and induces endothelial cytotoxicity and inflammation in a 3D human vessel-on-a-chip.Sci Rep. 2024 Aug 9;14(1):18553. doi: 10.1038/s41598-024-69124-w. Sci Rep. 2024. PMID: 39122790 Free PMC article.
-
Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation.Pharmaceutics. 2021 Jun 9;13(6):857. doi: 10.3390/pharmaceutics13060857. Pharmaceutics. 2021. PMID: 34207666 Free PMC article.
-
Severe ARDS Complicating an Acute Intentional Cresol Poisoning.Case Rep Crit Care. 2019 Aug 20;2019:6756352. doi: 10.1155/2019/6756352. eCollection 2019. Case Rep Crit Care. 2019. PMID: 31531245 Free PMC article.
-
Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release.Toxicol Rep. 2014 Dec 6;2:194-202. doi: 10.1016/j.toxrep.2014.11.019. eCollection 2015. Toxicol Rep. 2014. PMID: 28962351 Free PMC article.
-
Metabolism and toxicity of menthofuran in rat liver slices and in rats.Chem Res Toxicol. 2010 Nov 15;23(11):1824-32. doi: 10.1021/tx100268g. Epub 2010 Oct 14. Chem Res Toxicol. 2010. PMID: 20945912 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources