High variability of nitrosamine metabolism among individuals: Role of cytochromes P450 2A6 and 2E1 in the dealkylation of <i>N</i>‐nitrosodimethylamine and <i>N</i>‐nitrosodiethylamine in mice and humans

Camus, Anne-Marie; Geneste, Olivier; Honkakoski, Paavo; Béréziat, Jean‐Claude; Henderson, Colin J.; Wolf, C. Roland; Bartsch, Helmut; Lang, Matti A.

doi:10.1002/mc.2940070410

Cited by 135 publications

(76 citation statements)

References 28 publications

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“…The substrates include nitrosamines, aflatoxin B1, the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nicotine, 3-methylindole, methimazole, and acetaminophen Camus et al, 1993;Kirby et al, 1994aKirby et al, , 1996Pelkonen et al, 1994;Genter et al, 1998;Felicia et al, 2000;Siu et al, 2006;Xie et al, 2011;Zhou et al, 2012). A wide range of atypical CYP inducers of CYP2A5 has also been identified.…”

Section: Substrates and Inducers For Cyp2a5mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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Section: Substrates and Inducers For Cyp2a5mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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“…38 Increased CYP2A expression is also present at the periphery of cirrhotic nodules caused by O. viverrini infestation in hamster livers. 17 Similar events also occur in humans, because increased expression of CYP2A6 has been found in hepatocytes immediately adjacent to areas of fibrosis and inflammation in cirrhotic liver 10 and in livers infected with HBV and hepatitis C virus. 22 These observations are corroborated in the present study, in which a chronic inflammation and cirrhosis caused by hepatic tumors was associated with increased hepatocellular CYP2A6 content.…”

Section: Discussionmentioning

confidence: 82%

“…19,20 Recent studies indicate that human liver CYP2A6 is also induced by O. viverrini infestation, 21 and an elevated level of CYP2A6 protein was found in hepatocytes expressing the HBV surface antigen. 22 CYP2A mRNA has been shown to be expressed at higher levels in hepatocytes adjacent to areas of fibrosis in cirrhotic livers, 10 but no information exists on CYP2A6 regulation in human liver tumors. This study was performed to find out whether human hepatocellular carcinomas (HCC) exhibit elevated levels of CYP2A6 protein and to assess whether hepatic inflammatory processes affect liver CYP2A6 content.…”

mentioning

confidence: 99%

Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma

et al. 1998

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The hepatic cytochrome P4502A6 (CYP2A6) enzyme mediates the oxidative metabolism of several procarcinogens that have liver as their primary target. Mouse models indicate that liver tumors invariably overexpress CYP2A forms, and that inflammation and cirrhosis may regulate the CYP2A expression pattern. In this study, the distribution of the CYP2A6 protein was investigated in a series of 24 human hepatocellular carcinoma (HCC) samples by immunohistochemical analysis. A polyclonal antibody was raised in chicken against CYP2A5, the mouse orthologue of CYP2A6. The antibody was characterized and found to be specific for CYP2A members. In DBA/2 mouse liver, a strong increase of CYP2A5 protein amount, localized in the perivenous region, occurred in response to treatment with pyrazole. In human HCC samples, overexpression of CYP2A6 protein was associated with the presence of chronic inflammation and cirrhosis. CYP2A6 protein was observed in 9 of 16 (56%) of samples with non-neoplastic hepatocytes and in 10 of 24 (42%) HCC samples. The staining for CYP2A6 protein was very heterogeneous in tumor cells, suggesting that increased expression of CYP2A6 occurred in a distinct subpopulation of neoplastic cells. In Kaplan-Meyer survival analysis, there was a tendency toward a more favorable prognosis in patients with CYP2A6-positive tumors in comparison with patients with CYP2A6-negative tumors. These data suggest that, in human HCC, in contrast to mouse liver tumors, CYP2A6 overexpression is not an invariable phenotype. (HEPATOLOGY 1998;27:427-432.) Cytochrome P450 (CYP) enzymes mediate the oxidative metabolism of numerous exogenous and endogenous compounds. 1 It is well established that several CYP forms participate in the chemical carcinogenesis process by metabolically activating procarcinogens to reactive, DNA-binding intermediates. 2 The human CYP2A6 is one such form. 3 Like most other CYPs, CYP2A6 is most abundant in liver, and its levels in extrahepatic tissues are very low. 4,5 The CYP2A6 enzyme catalyses the metabolic activation of several procarcinogens and promutagens, including the liver-specific carcinogen aflatoxin B 1 , 6-8 several nitrosamines, 9-11 and 1,3-butadiene. 12 CYP2A6 is also a major catalyst in the oxidative metabolism of nicotine and cotinine, 13 as well as several pharmaceuticals. 14 The regulation of expression of members in the CYP2A subfamily differs markedly from other CYP forms. Studies on CYP2A5, the mouse orthologue of CYP2A6, have revealed that it is inducible by a variety of structurally dissimilar compounds, including phenobarbital, some heavy metals, heterocyclic nitrogen-containing agents, and various hepatotoxins including cocaine. 3,15,16 Animal studies have also shown that the expression of hepatic CYP2As is up-regulated by various types of biological insults, such as infestation with the liver fluke Opisthorchiasis viverrini 17 and integration of hepatitis B virus (HBV) to hepatocyte DNA. 18 In these animal models, CYP2A induction is associated with chronic inflammation in the liver t...

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“…Different cytochrome P450-dependent monooxygenases, including CYP2A and CYP2B groups and CYP2E1, are considered to be key enzymes involved in the activation or inactivation of NDEA. The extent of this biotransformation depends on the tissue specific availability of the necessary P450 isoenzymes (Camus et al, 1993). Metabolic activation can lead to the local formation of DNA adducts, impairment of bases and DNA breaks (Camus et al, 1993;Koskela et al, 1999;Aiub et al, 2003Aiub et al, , 2004a.…”

Section: Cyp Expressionmentioning

confidence: 99%

N-nitrosodiethylamine genotoxicity evaluation: a cytochrome P450 induction study in rat hepatocytes

Aiub¹,

Gadermaier²,

Silva³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. In rats, N-nitrosodiethylamine (NDEA) induces tumors mainly in the liver. This could be because various enzymes are responsible for the metabolic activation of NDEA, besides the hepatic NDEA metabolizing enzyme, CYP2E1. We examined NDEA genotoxicity and cytotoxicity in primary cultures of female rat hepatocytes; we also looked at how it affected CYP mRNA expression. Single incubation with 0.9% NaCl resulted in a mean of 0.2% apoptotic cells, which doubled with 105 µg NDEA/mL. The frequency of necrosis with NDEA treatment was also doubled. Besides the cytotoxic effects, there was also a 4-fold decrease in mitotic index and a 3-fold decrease in the percentage of cells with micronuclei. A significant increase in micronucleus cells when hepatocytes were incubated with 2.1 µg NDEA/mL suggests that DNA repair was inactive. The chromosomal aberration evaluation revealed a discrete dose-response curve. Treatment with NDEA 2341 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 10 (4): 2340-2348 (2011) N-nitrosodiethylamine and cytochrome P450 induction induced increases in CYP mRNA: CYP2B2 (1.8 times) and CYP2E1 (1.6 times) with non-cytotoxic NDEA concentrations (0.21-21 µg/mL). CYP2B1 mRNA levels decreased at 0.21 µg NDEA/mL (2.5-fold), while CYP4A3 mRNA decreased 1.3-fold. NDEA treatment at 2.1 µg/ mL induced a 1.9-fold increase in CYP3A1 mRNA. Understanding the cumulative effects in target cells during precarcinogenesis is crucial to understanding the mode of action of potential carcinogens and in order to develop comprehensive chemical toxicity profiles.

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High variability of nitrosamine metabolism among individuals: Role of cytochromes P450 2A6 and 2E1 in the dealkylation of N‐nitrosodimethylamine and N‐nitrosodiethylamine in mice and humans

Cited by 135 publications

References 28 publications

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma

N-nitrosodiethylamine genotoxicity evaluation: a cytochrome P450 induction study in rat hepatocytes

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