Sex‐ and strain‐specific expression of cytochrome P450s in Ochratoxin A‐induced genotoxicity and carcinogenicity in rats

Abstract

Ochratoxin A (OTA), a nephrotoxic and carcinogenic mycotoxin, is implicated in the etiology of Balkan endemic nephropathy (BEN), a chronic disease affecting populations in the Balkans. Patients suffering from Balkan endemic nephropathy, urinary-tract tumors, or both are more frequently extensive metabolizers of debrisoquine than persons unaffected by these conditions. As shown previously (Castegnaro et al., Int J Cancer, 77:70-75, 1998), OTA induction of renal tumors is markedly sex- and strain-specific in Dark Agouti (DA) and Lewis rats, with DA males being most responsive and DA females being resistant; only DA females were phenotyped as slow debrisoquine metabolizers. Formation of OTA-related DNA adducts in the kidney was closely correlated with renal carcinogenicity. To elucidate the critical biotransformation enzymes involved in OTA genotoxicity and carcinogenicity, the expression of cytochrome P450s (CYPs) 1A, 2A, 2B, 2C, 2D, and 3A in the kidney and liver microsomes of untreated and OTA-treated DA and Lewis rats (both sexes) was determined by western blot analysis. Chronic OTA treatment was found to modify CYP expression in kidney and liver. In the animals most susceptible to renal OTA carcinogenicity and DNA adduct formation, the OTA-toxifying isoforms (CYPs 2C11, 1A2, and 3A) were highly expressed in the liver, and little of the OTA-detoxifying isoforms (CYPs 1A1 and 2A) was detected. CYP2D was not expressed in DA rats and therefore is not involved in these phenomena. Our results confirm that the strain- and sex-specific genotoxic response of OTA is controlled, in part, by CYP-mediated metabolic reactions that convert OTA into DNA-reactive intermediates.

Modulation of the xenobiotic transformation system and inflammatory response by ochratoxin A exposure using a co-culture system of Caco-2 and HepG2 cells

“…In terms of gene expression, Ayed-Boussema et al 2012 in the liver and kidney from male Fisher-344 rats. In Dark Agouti rats of both sexes, only CYP3A4 expression was detected in male livers after OTA treatment, and CYP1A expression was higher than CYP2A (Pfohl-Leszkowicz et al, 1998), as in our in vitro assay.…”

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

“…The CYP 3A5*1 allele was more prevalent in BEN patients with a frequency of 9.38% compared to 5.36% in controls and was associated with a higher risk for BEN (OR 2.41). Our studies have also shown that in male DA rats that are highly susceptible to OTA-mediated renal carcinogenesis that the OTA-toxifying enzymes (CYP450 2C11, 1A2, and 3A) were highly expressed in the liver [220]. The induction of CYP2C11 in the DA rat is also highly relevant.…”

An Update on Direct Genotoxicity as a Molecular Mechanism of Ochratoxin A Carcinogenicity

“…Overall, Vettorazzi and co-workers observed no significant differences between males and females regarding OTA concentrations in kidney and liver . Given the lack of evidence showing greater exposure of male kidney to OTA, they suggested that differences in kidney or liver metabolism between both sexes could explain the higher sensitivity of male rats to OTA nephrocarcinogenicity, as originally proposed by Pfohl-Leszkowicz and co-workers …”