Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione-S-transferase

Adlouni, Chakib El; Pinelli, Éric; Azémar, Brigitte; Zaoui, Driss; Beaune, Philippe; Pfohl‐Leszkowicz, Annie

doi:10.1002/(sici)1098-2280(2000)35:2<123::aid-em7>3.3.co;2-c

Cited by 21 publications

(29 citation statements)

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“…This adduct is dechlorinated and thus could be formed only after OTA biotransformation [21,22,27,29,30]. The susceptibility of male rats to kidney cancer after OTA exposure is highly dependent on enzymes regulated by sexual hormones such CYP 2C [28] but also on enzymes involved in oxidative pathways [21] such cyclooxygenases [32,33,34] and glutathione conjugation [27,35]. Interestingly, Verma & Chakraborty [36] observed a decrease of catalase, SOD, glutathione peroxidase activities and of the amount of glutathione in testis of mice exposed to OTA.…”

Section: Discussionmentioning

confidence: 99%

Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA

Jennings-Gee

Tozlovanu

Manderville

et al. 2010

Toxins

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Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis. We tested the hypothesis that acute exposure to OTA, via food and via exposure in utero, causes adducts in testicular DNA and that these lesions are identical to those that can be produced in the kidney and testis by the consumption of OTA. Adult mice received a single dose of OTA (from 0–1,056 µg/kg) by gavage. Pregnant mice received a single i.p. injection of OTA (2.5 mg/kg) at gestation day 17. DNA adducts were determined by 32P-postlabeling. Gavage-fed animals sacrificed after 48 hours accumulated OTA in kidney and testis and showed DNA adducts in kidney and testis. Some OTA metabolites isolated from the tissues were similar in both organs (kidney and testis). The litters of mice exposed prenatally to OTA showed no signs of overt toxicity. However, newborn and 1-month old males had DNA adducts in kidney and testis that were chromatographically similar to DNA adducts observed in the kidney and testis of gavage-fed adults. One adduct was identified previously as C8-dG-OTA adduct by LC MS/MS. No adducts were observed in males from dams not exposed to OTA. Our findings that in utero exposure to OTA causes adducts in the testicular DNA of male offspring support a possible role for OTA in testicular cancer.

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Section: Discussionmentioning

confidence: 99%

Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA

Jennings-Gee

Tozlovanu

Manderville

et al. 2010

Toxins

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“…In a number of 32 P-postlabelling studies, lesions detected have been interpreted as being OTA-derived DNA adducts in cells or cell-free extract from animals and humans (Pfohl-Leszkowicz et al, 1993; Grosse et al, 1995; El Adlouni et al, 2000), as well as in vivo in rodents (Pfohl-Leszkowicz et al, 1991, 1993; Faucet et al, 2004; Pfohl-Leszkowicz and Castegnaro, 2005; Manderville, 2005). In these studies, however, the identity of the DNA adducts has not been clearly established and it is not known whether in fact the alleged DNA adducts actually contain the OTA moiety.…”

Section: Dna Adduct Formationmentioning

confidence: 99%

A reassessment of risk associated with dietary intake of ochratoxin A based on a lifetime exposure model

Haighton

Lynch

Magnuson

et al. 2012

Critical Reviews in Toxicology

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Mycotoxins, such as ochratoxin A (OTA), can occur from fungal growth on foods. OTA is considered a possible risk factor for adverse renal effects in humans based on renal tumors in male rats. For risk mitigation. Health Canada proposed maximum limits (MLs) for OTA based largely on a comparative risk assessment conducted by Health Canada (Kuiper-Goodman et al., 2010), in which analytical data of OTA in foods were used to determine the possible impact adopting MLs may have on OTA risks. The EU MLs were used for comparison and resultant risk was determined based on age–sex strata groups. These data were reevaluated here to determine comparative risk on a lifetime basis instead of age strata. Also, as there is scientific disagreement over the mechanism of OTA-induced renal tumors, mechanistic data were revisited. On a lifetime basis, risks associated with dietary exposure were found to be negligible, even without MLs, with dietary exposures to OTA three to four orders of magnitude below the pivotal animal LOAEL and the TD05. Our review of the mechanistic data supported a threshold-based mechanism as the most plausible. In particular, OTA was negative in genotoxicity assays with the highest specificity and levels of DNA adducts were very low and not typical of genotoxic carcinogens. In conclusion, OTA exposures from Canadian foods do not present a significant cancer risk.

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“…The retention time of this metabolite corresponded to that of a metabolite exclusively formed by in vitro incubation of OTA in the presence of microsomes from rabbits pre-treated with phenobarbital [6], and corresponds to 10-OH-OTA which is not genotoxic.…”

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confidence: 82%

“…The hypothesis of CYP P450 epoxygenase being implicated in the formation of these metabolites was confirmed by their disappearance when CYP P450 epoxygenase is inhibited (e. g. pre-treatment with NDGA or 10 lM indomethacin). These metabolites are particularly important because they were generated exclusively in BEAS-2B cells specifically expressing CYP 2C9 [6], a CYP highly involved in OTA genotoxicity and carcinogenicity in rats [5]. Thus, the pathway which seems to be implicated in their formation is CYP P450 epoxygenase.…”

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Answer to the Letter to the Editor of Prof. Degen

Pfohl‐Leszkowicz¹

2007

Molecular Nutrition Food Res

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We thank Prof. Degen for her careful reading of our paper. We do not think that it is really a misunderstanding.The sentence should not be taken out of context. Moreover we indicated that different data clearly imply a PEROXY-DASIC pathway (not specifically prostaglandin synthase PGHS, also known as cyclooxygenase 1 COX1). We explained and demonstrated in our different papers that the two major pathways involved in the biotransformation leading to genotoxicity of OTA are: (i) co-oxidation via the lipoxygenase pathway, and (ii) co-oxidation via CYP epoxygenase. Perhaps the explanation for this conclusion was too brief and requires some clarification.The results obtained by Degen et al.[1], who observed a proportional increase of micronuclei formation in ovine cells treated simultaneously with increasing amounts of indomethacin and OTA appear at first glance to be contradictory to our results. On the contrary, our results, in the same range of relative indomethacin/OTA concentrations, are in complete agreement and also confirm the results obtained in vivo [2]. In fact, in the presence of 10 lM indomethacin and 16 lM OTA, Degen et al. DID NOT OBSERVE micronuclei formation, which correlates well with the in vivo study (9 lM indomethacin and 15 lM OTA, [2]) and our experiment in which total inhibition of DNA adduct formation was obtained when cells were treated with 10 lM of each compound. Degen et al.[1] interpreted their results as a competition between indomethacin and OTA for plasma protein binding. In fact, this could be partially involved as more free OTA would be available. Nevertheless, this is not the sole event and could not explain the other results obtained with either low dose of indomethacin, NDGA or epinephrine [3]. It is noteworthy that micronuclei in ovine seminal vesicle cells are observed only when cells were treated with 33 lM OTA, a dose which causes high cytotoxicity and inhibition of repair enzyme. Another major discrepancy between our model and theirs is the presence of the Ah receptor in the ovine cells. The induction of this receptor led to expression of CYP 1A isoforms. We have shown that the CYP 1A family was induced by OTA and implicated in its genotoxicity [4,5]. Thus, the results obtained in ovine cells could be due to an increase of toxifying CYP (1A), in conjunction with a decrease of PROTECTING enzymes such as PGHS. In our model, a close parallel between inhibition of lipoxygenases and/or CYP P450 epoxygenases pathways, and a decrease of OTA genotoxicity induced by pre-treatement with 10 lM indomethacin or NDGA were observed, whereas inhibition of some PGHS pathways is in relation with an increase of genotoxicity (0.1 lM epinephrin or indomethacin).Interestingly, the OTA derivatives formed with pig microsomes are similar to those obtain under culture cell conditions where lipoxygenase and CYP P450 epoxygenase activities were predominant compared to PGHS (i. e. cells pre-treated with 0.1 lM indomethacin or epinephrine). The hypothesis of CYP P450 epoxygenase being implicated in the for...

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Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione-S-transferase

Cited by 21 publications

References 0 publications

Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA

Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA

A reassessment of risk associated with dietary intake of ochratoxin A based on a lifetime exposure model

Answer to the Letter to the Editor of Prof. Degen

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