Induction of specific cytochrome P450s involved in aflatoxin B<sub>1</sub> metabolism in hepatitis B virus transgenic mice

Kirby, Gordon M.; Chemin, Isabelle; Montesano, Ruggero; Chisari, Francis V.; Lang, Matti A.; Wild, Christopher P.

doi:10.1002/mc.2940110204

Cited by 91 publications

(64 citation statements)

References 18 publications

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“…41 Although injection of AFB 1 after weaning (1 month of age) is not carcinogenic for nontransgenic C57BL/6 mice, 25,26 in a previous study, AFB 1 -treatment of lineage 50-4 female mice at 3 months of age resulted in accelerated tumor development. 34 This was unexpected because liver injury and increased cellular proliferation associated with retention of HBsAg in transgenic mice does not occur until after 6 months of age.…”

Section: Discussionmentioning

confidence: 92%

“…There is increased expression and altered distribution of Cyp2a-5 in transgenic mice expressing HBsAg, and the increase in Cyp2a-5 correlates with the development of liver injury in mice and with age. 41 Cyp2a-5 is a highly conserved mouse cytochrome P450 isoenzyme that is important in AFB 1 metabolism and shares homology and catalytic properties with human CYP2A6. In addition, Cyp-3a, which is another P450 enzyme involved in AFB 1 metabolism was shown to also be increased in HBV-transgenic mice, but the increase was not clearly related to age.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the ␣-GST isoenzyme, YaYa, which confers part of the mouse resistance to the toxic and carcinogenic effect of AFB 1 was unchanged in these mice. 41 Effect of Loss of p53. Mice exposed to three risk factors: hepatitis B surface antigen expression (HBsAgϩ), loss of p53 allele (p53ϩ/Ϫ), and aflatoxin exposure, of both genders, showed more high grade tumors than any of the other groups.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Ghebranious

Sell

1998

Hepatology

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The objective of the present study is to develop experimental models in mice to study the role of the four major risk factors for development of hepatocellular carcinoma (HCC) in humans. The major risk factors are: hepatitis B infection, male gender, aflatoxin exposure, and p53 gene loss or mutation. HCC is the predominant cause of cancer mortality of males in Sub-Saharan Africa and Southern China. 1-3 It causes 65% to 75% of all cancer deaths in males and 30% to 55% of cancer deaths in females in Mozambique and some provinces of Southern China. [4][5][6][7] Epidemiological studies have identified infection with hepatitis B or C virus and contamination of grains with aflatoxin B 1 (AFB 1 ) as major and possibly synergistic risk factors in these areas. 2 Individuals with chronic hepatitis B virus (HBV) infection have a 200-fold greater risk of developing HCC than age-matched noninfected controls. 8 Of particular interest in regard to the relative importance of chronic hepatitis and AFB 1 is the geographical distribution of liver cancer in China. It is very uneven and does not follow closely the incidence of chronic hepatitis, but does follow the areas of aflatoxin contamination of ground nuts. 9

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Ghebranious

Sell

1998

Hepatology

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“…Transgenic mice harboring the gene for HBV surface antigen develop a progressive liver injury caused by accumulation of the antigen, and a concomitant emergence of CYP2A5-positive hepatocytes can be observed throughout the acinus. 18 In the HBV transgenic mouse lineage 107.5, HBV surface antigen is expressed at noncytopathic concentrations, but, when treated with a cytotoxic T-lymphocyte clone, the mice develop a severe necroinflammatory liver disease that is accompanied by CYP2A5 induction. 38 Increased CYP2A expression is also present at the periphery of cirrhotic nodules caused by O. viverrini infestation in hamster livers.…”

Section: Discussionmentioning

confidence: 99%

“…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 tissue. In addition, liver tumors in mice contain highly elevated levels of CYP2A5.…”

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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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Allele-specific PCR analysis ofp53 codon 249 AGT transversion in liver tissues from patients with viral hepatitis

et al. 1996

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AGG to AGT mutations in codon 249 of the p53 tumorsuppressor ene are frequently observed in hepatocellular carcinomas ~HCC) from areas where exposure to anatoxin B, (AFB) occurs. We developed a sensitive allele-specific polymerase chain reaction (AS-PCR) assay to detect this point mutation in non-neoplastic human liver tissues. Three oligonucleotide primers, I specific for the mutant allele and 2 specific for the wild-type allele were used. The mutant allele primer differed from the wild-type allele due to a G-to-T transversion in its terminal 3' nucleotide. The first stage invoked amplification of =on 7 of p53 followed by a selective amplification of mutant codon 249 sequences. This method allowed for the detection of a mutant codon 249 allele in the presence of as many as 10s copies of the wildallele and was 106-fold more sensitive than the restriction%gment length polymorphism-PCR techni ue. We have applied this AS-PCR protocol to examine codon 248 AGT transversion in tumor and matched non-tumor liver samples from North American patients with hepatitis and from Mozambi uan patients exposed to AFB. Mutations were detected i n 1 of 6 samples of non-neoplastic liver from Mozambican patients, all of whom were HBsAg-or HBcAg-positive and AFB-exposed. In contrast, no mutations were detected in non-neaplastic liver from North American patients with either HBV-or HCV-derived hepatitis and cirrhosis. This rocedure is a simple and powerful approach for screening pS! codon 249 AGT mutation in heterogeneous non-neoplastic hepatoqte 3~ Wiley-Liss, Inc. ulatiom.Hepatocellular carcinoma (HCC) is a major cause of mortality in areas, such as southern China and Africa, with high dietary levels of aflatoxin B1 (AFB) (Beasely, 1988; Harris, 1990;Montesano and Kirby, 1994). A "hot-spot'' mutation (G:C to T A transversion) at codon 249 of the p53 tumorsuppressor gene occurs in over 50% of HCC in areas where exposure to AFB is high, suggesting that AFB is an important causative mutagen Hsu et al., 1991). AGT mutation is induced in AFB-exposed human hepatocytes in culture, further supporting the role of AFB inp53 mutagenesis and HCC development (Aguilar et al., 1993). In addition to AFB, hepatic diseases associated with chronic inflammation and regenerative changes, such as viral hepatitis (hepatitis viruses B and C; HBV, HCV) and alcoholic cirrhosis, are important risk factors in neoplastic transformation early in the development of HCC (Beasley, 1988; Harris, 1990). Epidemiological studies have suggested a possible synergism between HBV infection and AFB exposure in hepatocellular carcinogenesis (Ross et al., 1992). However, the mechanisms have not been elucidated. A common mechanistic explanation for this association is that cellular proliferation during chronic active hepatitis allows for mutations, such as codon 249 ACT transversion, to become fixed, with subsequent selective clonal expansion of hepatocytes containing the mutation. However, there are other possible explanations for the involvement of HBV in ACT mutagenesis, i...

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Induction of specific cytochrome P450s involved in aflatoxin B₁ metabolism in hepatitis B virus transgenic mice

Cited by 91 publications

References 18 publications

Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma

Allele-specific PCR analysis ofp53 codon 249 AGT transversion in liver tissues from patients with viral hepatitis

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Induction of specific cytochrome P450s involved in aflatoxin B1 metabolism in hepatitis B virus transgenic mice

Cited by 91 publications

References 18 publications

Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma

Allele-specific PCR analysis ofp53 codon 249 AGT transversion in liver tissues from patients with viral hepatitis

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Induction of specific cytochrome P450s involved in aflatoxin B₁ metabolism in hepatitis B virus transgenic mice