• aflatoxin B1 biomarkers;
  • cytochrome P450s;
  • epoxide hydrolase;
  • glutathione-S-transferase;
  • p53 tumour suppressor gene;
  • transgenic mice;
  • woodchuck hepatitis virus


  1. Top of page
  2. Abstract
  3. Evidence for a synergistic hepatocarcinogenic interaction between AFB1 and HBV
  4. Possible mechanisms of interaction between AFB1 and HBV in hepatocarcinogenesis
  5. References

Abstract: Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1), two of the major risk factors in the multifactorial aetiology of hepatocellular carcinoma (HCC), co-exist in those countries with the highest incidences of and the youngest patients with this tumour, raising the possibility of a synergistic carcinogenic interaction between the two agents. Experimental studies in HBV-transgenic mice and woodchucks infected with woodchuck hepatitis virus were the first to show a synergistic hepatocarcinogenic effect between hepadnaviral infection and AFB1 exposure. With the availability of urinary and serum biomarkers that more accurately reflect dietary exposure to AFB1 than did the initially used food sampling and dietary questionnaires, cohort studies of patients with HCC in China and Taiwan have provided compelling evidence for a multiplicative or sub-multiplicative interaction between HBV and AFB1 in the genesis of human HCC. A number of possible mechanisms for the interaction have been suggested. Chronic HBV infection may induce the cytochrome P450s that metabolise inactive AFB1 to the mutagenic AFB1-8,9-epoxide. Hepatocyte necrosis and regeneration and the generation of oxygen and nitrogen reactive species resulting from chronic HBV infection increase the likelihood of the AFB1-induced p53 249ser and other mutations and the subsequent clonal expansion of cells containing these mutations. Nuclear excision repair, which is normally responsible for removing AFB1–DNA adducts, is inhibited by HBV×protein, favouring the persistence of existing mutations. This protein also increases the overall frequency of DNA mutations, including the p53 249ser mutation, and may contribute to uncontrolled cell cycling when p53 is non-functional.

The highest incidences of hepatocellular carcinoma (HCC) and the youngest patients with this tumour are found in China, Taiwan and sub-Saharan Africa, each of which is hyperendemic for hepatitis B virus (HBV) infection and has a high rate of dietary exposure to the fungal toxin, aflatoxin. Both chronic HBV infection and repeated exposure to aflatoxin B1 (AFB1) (the major component of aflatoxin mixtures typically found in foodstuffs contaminated by Aspergillus flavus or parasiticus and the most potent of the aflatoxins as an experimental hepatocarcinogen) are known to be major risk factors in the multifactorial aetiology of human HCC. A synergistic interaction between their carcinogenic effects offers a plausible explanation for the very high incidence of the tumour and the young age of the patients in these three countries or regions. This possibility has been investigated in recent years.

Evidence for a synergistic hepatocarcinogenic interaction between AFB1 and HBV

  1. Top of page
  2. Abstract
  3. Evidence for a synergistic hepatocarcinogenic interaction between AFB1 and HBV
  4. Possible mechanisms of interaction between AFB1 and HBV in hepatocarcinogenesis
  5. References

The earliest investigations into a possible causal association between the ingestion of foodstuffs contaminated with AFB1 and the development of HCC, although performed in geographical regions in which HBV infection was hyperendemic, did not include data on the concurrent HBV status of the populations studied. In two later studies, the roles of AFB1 exposure and HBV infection in explaining the varying frequencies of HCC in different areas of Swaziland (1) and the Guangxi Province of China (2) were assessed. Both analyses concluded that with simultaneous exposure to the two aetiological agents, AFB1 exposure was a more important determinant of geographical variation in the incidence of HCC than was HBV infection. However, no attempt was made to evaluate a possible interactive carcinogenic effect between the two risk factors.

The first published evidence consistent with synergism between AFB1 and HBV in the genesis of HCC was provided by experiments in which transgenic mice over-expressing the large envelope polypeptide of HBV were fed AFB1. These mice produced more rapid and extensive hepatocyte dysplasia and HCCs than did their unexposed littermates (3). Shortly thereafter, further experimental evidence for a positive interaction between AFB1 and another member of the Hepadnaviridae family, the woodchuck hepatitis virus (WHV), in the development of HCC was presented (4). In addition, woodchucks infected with WHV were shown to have enhanced activation of the biologically inactive AFB1 to the highly reactive and mutagenic metabolite, AFB1-8,9-epoxide (5). Other studies, however, failed to show increased activation of AFB1 to AFB1-8,9-epoxide (6) or an accelerated rate of HCC formation in WHV-infected woodchucks (7), although interpretation of the data in the latter study was hampered by the small number of surviving woodchucks (8). An increased number of HCCs was also reported in ducks infected with duck hepatitis virus and exposed to AFB1, although the number of animals studied was small.

Following the introduction of methods to measure aflatoxin metabolites and aflatoxin–DNA adducts in urine and aflatoxin–albumin adducts in serum, biomarkers that were a far more accurate and reliable indicator of AFB1 exposure than the hitherto used food sampling and dietary questionnaires (10), several large cohort studies were undertaken in Shanghai and Qidong counties, China and in Taiwan. All showed a synergistic interaction between exposure to AFB1 and the HBV carrier state in hepatocarcinogenesis (10–20). In four of the investigations, the relative risks of exposure to AFB1 alone, being a HBV carrier alone, and having the two risk factors together were calculated (Table 1). A striking multiplicative carcinogenic effect was evident in three of the studies (10–12) and a sub-multiplicative effect in the fourth (13). A dose–response effect was shown in one of the analyses (12).

Table 1.   Findings in four studies comparing the risk of HBV infection alone, dietary exposure to AFB1 alone and the two risk factors together in the genesis of HCC
 HBV aloneAFB1 aloneHBV and AFB1
RR (95% CL)*RR (95% CL)RR (95% CL)
  • HBV: hepatitis B virus; AFB1: aflatoxin B1; HCC: hepatocellular carcinoma.

  • *

    Relative risk (95% confidence limits).

Ross et al. (11)4.8 (1.2, 19.7)1.9 (0.5–7.5)60.1 (6.4–561.8)
Qian et al. (10)7.3 (2.2, 24.4)3.4 (1.1–10.0)59.4 (15.6–212)
Wang et al. (12)17.4 (3.6, 143.4)0.3 (0–3.6)70.0 (11.5–425.4)
Lunn et al. (13)17.0 (2.8, 103.9)17.4 (3.4, 90.3)67.6 (12.2, 373.2)

In other investigations, also in countries with high rates of contamination of foodstuffs by AFB1, only individuals chronically infected with HBV were studied and the influence of AFB1 exposure in further increasing their risk of HCC development was analysed. In Qidong County, China, over a 10-year prospective follow-up the risk of HCC in male carriers of the virus was shown to be increased 3.3-fold (95% confidence limits 1.2, 8.7) in those with detectable urinary levels of AFB1 metabolites (14). This result was confirmed in a longer observation of the same cohort of carriers, when the risk of HCC was increased 3.5-fold (95% confidence limits 1.5, 8.1) (15). A dose–response relationship between urinary AFB1 metabolites and risk of HCC was seen in HBV carriers in Taiwan. Comparing high and low urinary levels of the aflatoxin metabolite, AFM1, a multivariate-adjusted odds ratio of 6.0 (95% confidence limits 1.2, 29.0) was calculated. The risk was greater (odds ratio 10.0: 95% confidence limits 1.6, 60.9) when both AFM1 and AFB1–N7– guanine metabolites were measured in the urine (16). In a similar study performed in the same country, a statistically significant relationship was noted between detectable levels of AFB1-adducts in serum and the risk of HCC in chronic carriers of HBV, with an age-adjusted odds ratio of 2.0 (95% confidence limits 1.1, 3.7) (17).

The effect of a synergistic interaction between AFB1 and HBV on the age of onset of HCC was specifically addressed in a study of Taiwanese patients. HBV-infected patients in whom tumour tissue was shown by histochemical staining to be positive for AFB1–N7–guanine adducts were on average 10 years younger than those with adduct-negative tumours (18).

In some of the published studies, a positive interaction between HBV and AFB1 seemed to depend on the presence of a polymorphism of the phase II detoxification genes responsible for converting the carcinogenic AFB1-8,9-epoxide to non-reactive metabolites, the glutathione-S-transferase (GST) M1 and T1 and epoxide hydrolase (EPHX) genes. However, no consistent pattern has emerged. In one analysis in Taiwan, the risk of HCC formation was greater in HBV carriers who had the GST M1 null genotype compared with the non-null genotype (16), in a second the risk appeared to depend on the presence of a GST T1 null genotype (17) and in a third the risk was considerably greater in those with null genotypes of both GST M1 and GST T1 (19). A multiplicative interaction in the genesis of HCC in West African and Chinese patients was demonstrated between HBV infection and mutations of the EPHX gene: patients without chronic HBV infection but with at least one EPHX mutant allele had a 3.3-fold increase in HCC risk, those with HBV infection but normal EPHX alleles a 15-fold increase in risk and those with both HBV infection and at least one EPHX mutant allele a 77-fold increased risk (20).

The presence of a guanine to thymine transversion at the third base of codon 249 of the p53 tumour suppressor gene (arginine to serine substitution; 249ser) has been found in as many as 60% of HCCs from patients in regions with heavy dietary exposure to AFB1 (21,22). A specific causative association between this inactivating mutation and the presence of AFB1 biomarkers was later confirmed in epidemiological studies in regions with high or low AFB1 exposure rates (23,24). Arising from this observation, the presence of the 249ser mutation has been used as a permanent marker of dietary exposure to AFB1 in some studies of the interactive effects between the mycotoxin and HBV. The findings have, however, been inconsistent. In an investigation of Taiwanese patients with HCC, all the 249ser mutations occurred in patients positive for HBsAg, giving an odds ratio of 10.0 (95% confidence limits 1.6; 17.5) (13). Similarly, in a study in Qidong County, China, all the HCC patients with 249ser mutations showed evidence of chronic HBV infection (15), and in a second analysis in Taiwan the mutation was present in 36.3% of HBV-infected patients with HCC compared with 11.7% of those without HBV markers (12). Other studies revealed a similar but non-significant trend (24, 25), and in the remaining analyses from a variety of countries no association could be found (listed in 26). Moreover, in a meta-analysis of 49 published studies using a method that takes into account both within-study and study-to-study variabilities, little evidence for HBV–AFB1 interaction in modulating the 249ser mutation was found (26).

In summary, persuasive evidence that AFB1 and HBV interact synergistically in the genesis of HCC has accumulated. Indeed, based on the evidence now available it is not inconceivable that AFB1 may be an independent risk factor at very high levels of dietary exposure, but that HBV is an obligatory co-carcinogen for the mycotoxin at low or moderately low levels of exposure.

Possible mechanisms of interaction between AFB1 and HBV in hepatocarcinogenesis

  1. Top of page
  2. Abstract
  3. Evidence for a synergistic hepatocarcinogenic interaction between AFB1 and HBV
  4. Possible mechanisms of interaction between AFB1 and HBV in hepatocarcinogenesis
  5. References

Given that AFB1 and HBV are synergistic causative agents of HCC, what are the possible mechanisms for the interaction between the two risk factors? A number of mechanisms have been suggested. The first is that HBV infection directly or indirectly sensitises hepatocytes to the carcinogenic effects of AFB1. One way in which this may be accomplished is that the specific cytochrome P450s that metabolise AFB1 to AFB1-8,9-epoxide may be induced either by chronic hepatitis attributable to HBV or by the presence of the virus itself. Induction of these phase I enzymes has been described in HBV transgenic mice (6, 27), where this effect appeared to result from hepatocyte injury rather than the presence of the virus per se (27). The observation that Gambian children and adolescents chronically infected with HBV have higher concentrations of AFB1 adducts than uninfected individuals (28–30) is consistent with this mechanism, although because of the often asymptomatic nature of HBV carriage in these children, the virus itself is favoured as the cause. However, studies in adults in China, Taiwan and The Gambia have either failed to show a significant difference in serum AFB1–albumin adduct levels between HBsAg-positive and -negative subjects (31–33) or showed only a marginally significant difference (34), and woodchucks with chronic WHV infection did not show enhanced activation of AFB1 (7, 35). Another possibility is that the activity of phase II detoxification enzymes (GST and EPHX) may play a role in the genesis of HCC induced jointly by AFB1 and HBV (16, 17, 20).

In those populations in which an interaction between the fungal toxin and HBV has been described, the infection is predominantly acquired in infancy or early childhood. During the early stages of the infection, a state of immune tolerance towards the virus exists and little if any cellular damage occurs. With loss of tolerance, chronic hepatitis with recurring cell damage develops. Exposure to AFB1 in contaminated foodstuffs also occurs in young children (36), although it is not known at what age precisely this commences. Nevertheless, it is likely, certainly in China and Taiwan, where perinatal transmission of HBV is the predominant mode of infection, and also probably in Africa, where slightly later horizontal infection is the major route of infection, that the HBV carrier state is established before heavy exposure to AFB1. The exact timing of the development of the 249ser mutation remains uncertain, although it is known to be an early event. This mutation abrogates the normal functions of p53, including those in cell cycle control, DNA repair and apoptosis, thereby contributing to the multistep process of hepatocarcinogenesis. The second possible mechanism of a carcinogenic interaction between AFB1 and HBV is that increased hepatocyte necrosis and proliferation caused by chronic HBV infection increases the likelihood of both AFB1-induced mutations, including 249ser and the subsequent clonal expansion of cells containing these mutations (37).

Thirdly, chronic necroinflammatory hepatic disease, including that resulting from HBV infection, results in the generation of oxygen and nitrogen reactive species (38, 39). Both of the latter are mutagenic but, in addition, increased oxidative stress has been shown to induce the 249ser mutation (40).

Finally, AFB1–DNA adducts are normally repaired by the nucleotide excision repair pathway. The HBV×gene is frequently included in sequences of the virus that are integrated into cellular DNA. The HBV×protein interferes with the nucleotide excision repair pathway (41) and might, by this means, favour persistence of existing mutations. DNA repair is also compromised by the rapid cell turnover rate in chronic hepatitis. In the presence of dietary exposure to AFB1, the HB×protein may contribute to uncontrolled cell proliferation in other ways. The transcription of p21waf1/cip1, which induces cell cycle arrest at the G1–S checkpoint, is activated by HB×protein in a dose-dependent manner in the presence of functional p53. However, this transcription is repressed by HB×protein when p53 is not functional or functional at a low level (42). The expression of HB×protein also correlates with an increase in the overall frequency of DNA mutations in transgenic mice and a 2-fold increase in the incidence of the 249ser mutation in transgenic mice exposed to AFB1 (43).


  1. Top of page
  2. Abstract
  3. Evidence for a synergistic hepatocarcinogenic interaction between AFB1 and HBV
  4. Possible mechanisms of interaction between AFB1 and HBV in hepatocarcinogenesis
  5. References
  • 1
    Peers F, Bosch X, Kaldor J, Linsell A, Pleijmen M. Aflatoxin exposure, hepatitis B virus infection and liver cancer in Swaziland. Int J Cancer 1987; 39: 54553.
  • 2
    Yeh F-S, Yu M C, Mo C-C, Luo S, Tong M J, Henderson B E. Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res 1989; 49: 25069.
  • 3
    Sell S, Hunt J M, Dunsford H A, Chisari F V. Synergy between hepatitis B virus expression and chemical hepatocarcinogenesis in transgenic mice. Cancer Res 1991; 51L: 127885.
  • 4
    Bannasch P, Khoshkou N I, Hacker H J, et al. Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary aflatoxin B1 in woodchucks. Cancer Res 1995; 55: 331830.
  • 5
    De Flora S, Hietane E, Bartsch H, et al. Enhanced metabolic activation of chemical hepatocarcinogenesis in woodchucks infected with woodchuck hepatitis virus. Carcinogenesis 1989; 10: 1099106.
  • 6
    Gemechu-Hatewu M, Platt K-L, Oesch F, Hacker H J, Bannasch P, Steinberg P. Metabolic activation of aflatoxin B1 to aflatoxin B1-8,9-epoxide in woodchucks undergoing chronic active hepatitis. Int J Cancer 1997; 73: 58791.
  • 7
    Tennant B C, Hornbuckle W E, Yeager A E, et al. Effects of aflatoxin B1 on experimental woodchuck hepatitis virus infection and hepatocellular carcinomas. In: HollingerF B, LemonS M, MargolisH, eds. Viral Hepatitis and Liver Disease. Baltimore: Williams and Wilkins, 1990; 599600.
  • 8
    IARC. Hepatitis B virus. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 59. Lyon: IARC, 1994; 45164.
  • 9
    Cova L, Wild C P, Mehrotra R, et al. Contribution of aflatoxin B1 and duck hepatitis B virus in the induction of liver tumors in ducks. Cancer Res 1990; 50: 215663.
  • 10
    Qian G S, Ross R K, Yu M C, et al. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev 1994; 3: 310.
  • 11
    Ross R K, Yuan J M, Yu M C, et al. Urinary aflatoxin biomarkers and the risk of hepatocellular carcinoma. Lancet 1992; 339: 9436.
  • 12
    Wang L-Y, Hatch M, Chen C-J, et al. Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan. Br J Cancer 1996; 67: 62030.
  • 13
    Lunn R M, Zhang Y-J, Wang L-Y, et al. Mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res 1997; 57: 34717.
  • 14
    Sun Z, Lu P, Gail M H, et al. Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 1999; 30: 37983.
  • 15
    Ming L, Thorgeirsson S S, Gail M H, et al. Dominant role of hepatitis B virus and co-factor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology 2002; 36: 121420.
  • 16
    Yu M-W, Lien J-P, Chiu Y-H, Santella R M, Liaw Y-F, Chen C-J. Effect of aflatoxin metabolism and DNA adduct formation on hepatocellular carcinoma among chronic hepatitis B carriers in Taiwan. J Hepatol 1997; 27: 12030.
  • 17
    Sun C-A, Wang L-Y, Chen C-J, et al. Genetic polymorphisms of glutathione-S-transferases M1 and T1 associated with susceptibility to aflatoxin-related carcinogenesis among chronic hepatitis B carriers: a nested case–control study in Taiwan. Carcinogenesis 2001; 22: 128994.
  • 18
    Chen C J, Zhang Y J, Lu S N, Santella R M. Afaltoxin-B1-adducts in smeared liver tissue of hepatocellular carcinoma patients. Hepatology 1992; 16: 11505.
  • 19
    Chen C-J, Yu M-W, Liaw Y-F, et al. Chronic hepatitis B carriers with null genotypes glutathione-S-transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma. Am J Hum Genet 1996; 59: 12834.
  • 20
    McGlynn K A, Rosvold E A, Lustbader E D, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci USA 1995; 92: 23847.
  • 21
    Hsu I C, Metcalf R A, Sun T, Welsh J A, Wang N J, Harris C C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature (London) 1991; 350: 4278.
  • 22
    Bressac B, Kew M C, Wands J R, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature (London) 1991; 350: 42930.
  • 23
    Ozturk M, Bressac B, Pusieux A, et al. A p53 mutational hotspot in primary liver cancer is geographically localised to high aflatoxin areas of the world. Lancet 1991; 338: 2605.
  • 24
    Eaton D L, Gallagher E P. Mechanisms of aflatoxin carcinogenesis. Ann Rev Pharmacol Toxicol 1994; 34: 275301.
  • 25
    Sheu J-C, Huang G-T, Lee P-H, et al. Mutations of p53 in hepatocellular carcinomas in Taiwan. Cancer Res 1992; 52: 6098100.
  • 26
    Stern M C, Umbach D M, Yu M C, London S J, Zhang Z-Q, Taylor J A. Hepatitis B, aflatoxin B1, and p53 codon 249 mutation in hepatocellular carcinoma from Guangxi, People's Republic of China, and a meta-analysis of existing studies. Cancer Epidemiol Biomarkers Prev 2001; 10: 61725.
  • 27
    Chemin I, Ohgaki H, Chisari F V, Wild C P. Altered expression of hepatic carcinogen metabolizing enzymes with liver injury in HBV transgenic mouse lineages expressing various amounts of hepatitis B surface antigen. Liver 1999; 19: 817.
  • 28
    Allen S J, Wild C P, Wheeler J G, et al. Aflatoxin exposure, malaria and hepatitis B infection in rural Gambian children. Trans Roy Soc Trop Med Hyg 1992; 86: 42630.
  • 29
    Chen S-Y, Chen C-J, Chou S-R, et al. Association of aflatoxin B1-albumin adduct levels with hepatitis B surface antigen status among adolescents in Taiwan. Cancer Epidemiol Biomarkers Prev 2001; 10: 12236.
  • 30
    Turner P C, Mendy M, Whittle H, Fortuin M, Hall A J, Wild C P. Hepatitis B infection and aflatoxin biomarker levels in Gambian children. Trop Med Int Health 2000; 5: 83741.
  • 31
    Groopman J D, Hall A J, Whittle H, et al. Molecular dosimetry of aflatoxin-N7 –guanine in human urine obtained in The Gambia. Cancer Epidemiol Biomarkers Prev 1992; 1: 2217.
  • 32
    Wang J S, Qian G S, Zarba A, et al. Temporal patterns of aflatoxin-albumin adducts in hepatitis B surface antigen-positive and-negative residents of Daxin, Qidong County, People's Republic of China. Cancer Epidemiol Biomarkers Prev 1996; 5: 25361.
  • 33
    Chen S-Y, Chen C-J, Tsai W-Y, et al. Associations of plasma aflatoxin B1-albumin adduct level with plasma selenium level and genetic polymorphisms of glutathione-S-transferase M1 and T1. Nutr Cancer 2000; 38: 17985.
  • 34
    Sun C-A, Wu D-M, Wang L-Y, Chen C-J, You S-L, Santella RM. Determinants of formation of aflatoxin-albumin adducts: a seven township study in Taiwan. Br J Cancer 2002; 87: 96670.
  • 35
    Kirby G, Chemin I, Montesano R, Chisari F V, Lang M A, Wild C P. Induction of specific cyotochrome p-450s involved in aflatoxin B1 metabolism in hepatitis B transgenic mice. Mol Carcinogenesis 1994; 11: 7480.
  • 36
    Wild C P, Fortuin M, Donato F, et al. Aflatoxin, liver enzymes and hepatitis B virus infection in Gambian children. Cancer Epidemiol Biomarkers Prev 1993; 2: 55561.
  • 37
    Chisari F V, Klopchin K, Moriyama T, et al. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B transgenic mice. Cell 1989; 59: 114556.
  • 38
    Liu R H, Jacob J R, Hotchkiss J H, Cote P J, Gerin J L, Tennant B C. Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes: possible role in hepatocarcinogenesis. Carcinogenesis 1994; 15: 28757.
  • 39
    Ishima H, Bartsch H. Chronic infection and inflammatory processes as cancer risk factors: possible role for nitric oxide in carcinogenesis. Mutation Res 1994; 305: 25364.
  • 40
    Hussain S P, Aquilar F, Amstad P, Cerutti P. Oxy-radical induced mutagenesis of hotspot codons 248 and 249 of the human p53 gene. Oncogene 1994; 9: 227781.
  • 41
    Jia L, Wang X W, Harris C C. Hepatitis B virus×protein inhibits nucleotide excision repair. Int J Cancer 1999; 80: 8759.
  • 42
    Ahn J I, Jung E Y, Kwun H J, Lee C W, Sung Y C, Jang K L. Dual effects of hepatitis B virus × protein on the regulation of cell cycle depending on the status of cellular p53. J Gen Virol 2002; 83: 276572.
  • 43
    Madden C R, Finegold M J, Slagle B L. Altered DNA mutation spectrum in aflatoxin B1-treated transgenic mice that express the hepatitis B virus×protein. J Virol 2002; 76: 117704.