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

Abstract

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.

Novel Perspective on Mechanism in Muscle Growth Inhibited by Ochratoxin A Associated with Ferroptosis: Model of Juvenile Grass Carp (Ctenopharyngodon idella) In Vivo and In Vitro Trials

“…The residue of OTA in the body is mainly closely related to its biological transformation and transportation . AHR and its ligands AHRNT and PXR are the main enzymes responsible for metabolizing OTA, and AHR can activate downstream CYP1A and CYP3A enzymes .…”

“…The residue of OTA in the body is mainly closely related to its biological transformation and transportation. 45 AHR and its ligands AHRNT and PXR are the main enzymes responsible for metabolizing OTA, and AHR can activate downstream CYP1A and CYP3A enzymes. 45 Our results showed that as the OTA dose increased, the AHR, AHRNT, PXR, CYP1A, and CYP3A mRNA expressions significantly increased.…”

“…45 AHR and its ligands AHRNT and PXR are the main enzymes responsible for metabolizing OTA, and AHR can activate downstream CYP1A and CYP3A enzymes. 45 Our results showed that as the OTA dose increased, the AHR, AHRNT, PXR, CYP1A, and CYP3A mRNA expressions significantly increased. This is consistent with previous research: OTA increased AHR, PXR, CYP1A, and CYP3A in kidney cells 46 and liver cells.…”

New perspectives in application of kidney biomarkers in mycotoxin induced nephrotoxicity, with a particular focus on domestic pigs

“…However, in in vitro studies, these markers were not so suitable for the detection the nephrotoxic effects of OTA (Rached et al, 2008). On the contrary, OTA treatment was applied to mice where KIM-1 and NGAL were used to monitor the nephrotoxicity of the xenobiotics (Hassan et al, 2022). Studies have also been carried out using serum or blood samples collected to determine biochemical parameters which reflect kidney function (Mohd Redzwan et al, 2014).…”

“…Ochratoxins are a group of mycotoxins produced by Aspergillus species, e.g., Aspergillus niger as well as some Penicillium which can exert damage to organisms (Ringot et al, 2006). For example, OTA disrupts several cell functions, including cell proliferation, division, and signaling pathways (Vettorazzi et al, 2013;Hassan et al, 2022), it also has a synergistic effect on other co-occurring mycotoxins (Liu et al, 2022a).…”