Item request has been placed!
×
Item request cannot be made.
×
Processing Request
Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A.
Item request has been placed!
×
Item request cannot be made.
×
Processing Request
- المؤلفون: Hassan, Reham1,2 (AUTHOR); González, Daniela1 (AUTHOR); Hobloss, Zaynab1 (AUTHOR); Brackhagen, Lisa1 (AUTHOR); Myllys, Maiju1 (AUTHOR); Friebel, Adrian3 (AUTHOR); Seddek, Abdel-latif2 (AUTHOR); Marchan, Rosemarie1 (AUTHOR); Cramer, Benedikt4 (AUTHOR); Humpf, Hans-Ulrich4 (AUTHOR); Hoehme, Stefan3 (AUTHOR); Degen, Gisela H.1 (AUTHOR) ; Hengstler, Jan G.1 (AUTHOR) ; Ghallab, Ahmed1,2 (AUTHOR)
- المصدر:
Archives of Toxicology. Dec2022, Vol. 96 Issue 12, p3349-3361. 13p.
- الموضوع:
- معلومة اضافية
- نبذة مختصرة :
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. [ABSTRACT FROM AUTHOR]
No Comments.