Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A

• Published in: Archives of toxicology 2022-12, Vol.96 (12), p.3349-3361
• Main Authors: Hassan, Reham, González, Daniela, Hobloss, Zaynab, Brackhagen, Lisa, Myllys, Maiju, Friebel, Adrian, Seddek, Abdel-latif, Marchan, Rosemarie, Cramer, Benedikt, Humpf, Hans-Ulrich, Hoehme, Stefan, Degen, Gisela H., Hengstler, Jan G., Ghallab, Ahmed
• Format: Article
• Language: English
• Subjects: Acetaminophen; Alanine; Alanine transaminase; Aspartate transaminase; Biocompatibility; Biomarkers; Biomedical and Life Sciences; Biomedicine; Blood; Carbon tetrachloride; Contaminants; Cytochrome; Cytochrome P450; Cytochromes P450; Damage patterns; Detoxification; Environmental Health; Food contamination; Gelatinase; Hepatotoxicity; Intravenous administration; Kidneys; Leukocytes (neutrophilic); Lipocalin; Liver; Mycotoxins; Occupational Medicine/Industrial Medicine; Ochratoxin A; Organ Toxicity and Mechanisms; Pharmacology/Toxicology; Toxicity
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-022-03395-y

The mycotoxin ochratoxin A (OTA) is a contaminant in food that causes nephrotoxicity and to a minor degree hepatotoxicity. Recently, we observed that OTA induces liver damage preferentially to the cytochrome P450 (CYP)-expressing pericentral lobular zone, similar to hepatotoxic substances known to be metabolically toxified by CYP, such as acetaminophen or carbon tetrachloride. To investigate whether CYP influences OTA toxicity, we used a single dose of OTA (7.5 mg/kg; intravenous) with and without pre-treatment with the pan CYP-inhibitor 1-aminobenzotriazole (ABT) 2 h before OTA administration. Blood, urine, as well as liver and kidney tissue samples were collected 24 h after OTA administration for biochemical and histopathological analyses. Inhibition of CYPs by ABT strongly increased the nephro- and hepatotoxicity of OTA. The urinary kidney damage biomarkers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were increased > 126-fold and > 20-fold, respectively, in mice treated with ABT and OTA compared to those receiving OTA alone. The blood biomarkers of liver damage, alanine transaminase (ALT) and aspartate transaminase (AST) both increased > 21- and 30-fold, respectively, when OTA was administered to ABT pre-treated mice compared to the effect of OTA alone. Histological analysis of the liver revealed a pericentral lobular damage induced by OTA despite CYP-inhibition by ABT. Administration of ABT alone caused no hepato- or nephrotoxicity. Overall, the results presented are compatible with a scenario where CYPs mediate the detoxification of OTA, yet the mechanisms responsible for the pericental liver damage pattern still remain to be elucidated.