Hepatitis: Wild CP

Hall AJ, Wild CP. · No affiliation provided · BMJ. · Pubmed #12742895 links to  free full text

This publication has no abstract.

Groopman JD, Kensler TW, Wild CP. · Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Annu Rev Public Health. · Pubmed #17914931 No free full text.

Abstract: The public health impact of aflatoxin exposure is pervasive in economically developing countries; consequently, we need to design intervention strategies for prevention that are practicable for these high-risk populations. The adverse health consequences of aflatoxins in populations are quite varied, eliciting acute effects, such as rapid death, and chronic outcomes, such as hepatocellular carcinoma. Furthermore, a number of epidemiological studies describe a variety of general adverse health effects associated with aflatoxin, such as impaired growth in children. Thus, the magnitude of the problem is disseminated across the entire spectrum of age, gender, and health status in the population. The aflatoxins multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus (HBV), which illustrates the deleterious impact that even low toxin levels in the diet can pose for human health. Thus other aflatoxin interactions, which likely contribute to the disease burden, still remain to be identified. Therefore, many diverse and appropriate strategies for disease prevention are needed to decrease the incidence of aflatoxin carcinogenesis in developing countries.

Turner PC, Sylla A, Diallo MS, Castegnaro JJ, Hall AJ, Wild CP. · Molecular Epidemiology Unit, Epidemiology and Health Services Research, Algernon Firth Building, School of Medicine, University of Leeds, Leeds, UK. · J Gastroenterol Hepatol. · Pubmed #12534775 No free full text.

Abstract: Aflatoxins and hepatitis B virus (HBV) are major risk factors for hepatocellular carcinoma (HCC) in South-east Asia and Africa, parts of the world where this cancer is most prevalent. Exposure to both factors is endemic, occurring from early in life. There is evidence from both epidemiological studies and animal models that the two factors can act synergistically to increase the risk of HCC, but the underlying cellular and molecular mechanisms of interaction are as yet undefined. One possibility suggested by studies in HBV transgenic mice is that chronic liver injury alters the expression of carcinogen metabolizing enzymes, thus modulating the level of binding of aflatoxin to DNA. Primary prevention of HCC in high incidence areas of the world should primarily be focused on provision of the safe, effective vaccine against HBV. However, measures to reduce the high levels of aflatoxin exposure, where chronic HBV infection is currently epidemic, would also significantly contribute to reducing HCC incidence. In Guinea-Conakry, West Africa, surveys of HBV infection and aflatoxin exposure have established baseline data for the implementation of a community-based intervention study. This study will evaluate the effectiveness of improving the post-harvest processing and storage of the groundnut crop, a major source of aflatoxins, using aflatoxin-albumin adducts as the outcome measurement.

Wild CP, Turner PC. · Molecular Epidemiology Unit, Epidemiology and Health Services Research, Algernon Firth Building, School of Medicine, University of Leeds, Leeds LS2 9JT, UK. · Mutagenesis. · Pubmed #12435844 links to  free full text

Abstract: Aflatoxins have been extensively studied with respect to their mechanisms of toxicity. An understanding of metabolism, DNA adduct induction, mutagenicity and carcinogenicity has been paralleled by the development of biomarkers of aflatoxin exposure and biological effects (e.g. mutations) applied to human populations. The improvements in exposure assessment and their application in prospective epidemiological studies and the demonstration of a specific mutation in the TP53 gene in hepatocellular carcinomas from areas of high aflatoxin exposure have contributed significantly to the classification of aflatoxins as human carcinogens. In addition to establishing the carcinogenicity of aflatoxins in humans, understanding molecular mechanisms of action has provided the scientific rationale for prevention strategies, including primary and chemoprevention approaches. Overall, integrated, multidisciplinary research on aflatoxins has provided the platform on which to base decisions regarding acceptable exposures and priorities for interventions to reduce human risk in a public health context.

Wild CP, Turner PC. · Molecular Epidemiology Unit, Epidemiology and Health Services Research, School of Medicine, University of Leeds, UK. · IARC Sci Publ. · Pubmed #11220661 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, the major risk factors being hepatitis B and C viruses and aflatoxins; other factors such as alcohol are also of importance in some populations. Aflatoxin exposure biomarkers include urinary aflatoxin metabolites and aflatoxin-albumin adducts in peripheral blood. These biomarkers are well validated and have been applied in studies of many populations worldwide. They are proving to be valuable end-points in intervention studies, including chemoprevention studies. The biomarkers permit assessment of primary prevention measures to reduce aflatoxin intake. In addition, the determination of individual urinary aflatoxin metabolite profiles means that the effectiveness of chemopreventive agents designed to modulate aflatoxin metabolism can also be evaluated. Both aflatoxin-albumin adducts and urinary aflatoxin metabolites have been associated with increased HCC risk in prospective studies, indicating the predictive value of these biomarkers at the group level. However, given the multifactorial and multistep nature of HCC, it is unlikely that these exposure biomarkers will be predictive at the individual level or be of value as surrogate end-points in longer-term intervention trials aimed at reducing disease incidence. Aflatoxin-related mutations at codon 249 of the p53 gene in plasma may be more relevant in this regard but their application requires further understanding of the temporal appearance of this biomarker in relation to the natural history of the disease.

Wild CP, Hall AJ. · Molecular Epidemiology Unit, Algernon Firth Building, School of Medicine, University of Leeds, Leeds, UK. · Mutat Res. · Pubmed #10767647 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with 80% of cases occurring in developing countries. The cancer is rapidly fatal in almost all cases with survival generally less than 1 year from diagnosis. The major risk factors for this cancer have been identified as chronic infection with hepatitis B (HBV) and hepatitis C (HCV) viruses and dietary exposure to aflatoxins. There is a safe and effective vaccine to prevent chronic HBV infection. Given estimates that approximately 70% of HCC in developing countries is attributable to HBV then vaccination could prevent more than 250,000 cases per year in these areas of the world. A major challenge now is to ensure the availability of vaccine in countries with endemic infection. Development of a vaccine against HCV is more problematic due to the genetic heterogeniety of the virus. However, with 24% of HCC in developing countries attributable to HCV (approximately 93,000 cases per year) a vaccine would make a major contribution to cancer prevention. Aflatoxins contaminate dietary staple foods (groundnuts, maize), are potent animal hepatocarcinogens and are carcinogenic in humans with particularly high risks in individuals with a concomitant infection with HBV. Reduction of exposure can be addressed at the community level either pre- or post-harvest by limiting fungal contamination of crops; approaches may involve low technology post-harvest measures to limit fungal growth or genetic engineering of crops to be resistant to fungal infection or toxin biosynthesis. An alternative measure is to modulate the metabolism of aflatoxins once ingested using chemopreventive agents e.g., oltipraz. The resources available in countries with endemic hepatitis infection and fungal contamination of foods are often severely limited. Clearly HBV vaccination has to be the priority in the reducing the incidence of HCC. However, there are currently 360 million chronic HBV carriers worldwide and HBV vaccine is still not incorporated into many national immunisation programs. Thus measures to reduce food spoilage by fungi and the associated dietary exposure to aflatoxins is also a desirable public health goal.

Sylla A, Diallo MS, Castegnaro J, Wild CP. · Institut de Recherche Biologique Applique de Guinee (IRBAG), Kindia, Guinea. · Mutat Res. · Pubmed #10517992 No free full text.

Abstract: Aflatoxins and hepatitis B virus (HBV) are major risk factors for hepatocellular carcinoma (HCC) in high incidence areas for this cancer, namely southeast Asia and parts of Africa. There is evidence from both epidemiological studies and animal models that the two factors can act synergistically to increase the risk of HCC. The cellular and molecular mechanism of the interaction between these two factors is as yet undefined. However, one possible mechanism attested to by studies in HBV transgenic mice is that chronic liver injury alters the expression of specific carcinogen metabolising enzymes thus modulating the binding of aflatoxin to DNA in hepatocytes. The high levels of aflatoxin exposure which occur in many areas of the world where chronic HBV infection is endemic indicate that measures to reduce aflatoxin exposure would contribute to reducing HCC incidence. In preliminary studies, Guinea-Conakry have established baseline data for the implementation of a community-based intervention study to evaluate the effectiveness of improved post-harvest processing and storage of the groundnut crop, a major source of aflatoxins. Aflatoxin-albumin adducts were measured in 423 sera from individuals living in the four natural geographic zones of Guinea. More than 95% of the serum samples were positive for this biomarker and highest exposures were found in Lower Guinea where groundnuts are consumed as a dietary staple. Variations in mean levels between villages within a geographic region did not vary greatly. HBV infection was endemic in all regions with an overall prevalence of 16.7% chronic carriers. Thus in this population both HBV vaccination and reduction in aflatoxin exposure would be beneficial in decreasing morbidity and mortality from liver disease.

Polychronaki N, Wild CP, Mykkänen H, Amra H, Abdel-Wahhab M, Sylla A, Diallo M, El-Nezami H, Turner PC. · Department of Clinical Nutrition, University of Kuopio, Finland. · Food Chem Toxicol. · Pubmed #17920747 No free full text.

Abstract: Aflatoxins are a major risk factor for hepatocellular carcinoma (HCC), and thus understanding the pattern of aflatoxin exposure in different regions is important in order to develop targeted intervention strategies. Given the early onset of HCC in many countries early life exposures may be important. This study investigated aflatoxin exposure in Egyptian children (n=50, aged 1-2.5 years) by assessing urinary aflatoxin metabolite (AFM(1), AFB(1), AFB(2), AFG(1), AFG(2)) levels. Samples from Guinean children (n=50, aged 2-4 years) were analyzed in parallel providing a comparison to a region of established frequent aflatoxin exposure. Aflatoxins were isolated from urine using C18-cartridges followed by immunoaffinity clean-up, and quantified by HPLC with fluorescence detection. Overall aflatoxins were less frequently present in Egyptian (38%) than Guinean urine samples (86%) (p<0.001), which was particularly related to differences in detection rates of AFM(1) (8% compared to 64%, respectively, (p<0.001)). For AFM(1) the geometric mean level in Guinea (16.3 pg/ml; 95% CI: 10.1, 26.6 pg/ml) was 6-fold higher (p<0.001) than in Egypt (2.7 pg/ml; 95% CI: 2.5, 2.8 pg/ml). Urinary aflatoxins from healthy children in these two regions have not previously been reported, and exposure appears modest in Egypt compared to Guinea. These data suggest that measures to reduce aflatoxin exposure in both regions are important, though particularly in Guinea.

Szymañska K, Chen JG, Cui Y, Gong YY, Turner PC, Villar S, Wild CP, Parkin DM, Hainaut P. · IARC, Lyon Cedex 08, France. · Cancer Epidemiol Biomarkers Prev. · Pubmed #19366907 No free full text.

Abstract: Hepatocellular carcinoma (HCC) has a high mortality in East Asia and Sub-Saharan Africa, two regions where the main etiologic factors are chronic infections with hepatitis B virus and dietary exposure to aflatoxin. A single base substitution at the third nucleotide of codon 249 of TP53 (R249S) is common in HCC in these regions and has been associated with aflatoxin-DNA adducts. To determine whether R249S may be detected in plasma DNA before HCC diagnosis, we conducted a case-control study nested in a cohort of adult chronic hepatitis B virus carriers from Qidong County, People's Republic of China. Of the 234 plasma specimens that yielded adequate DNA, only 2 (0.9%) were positive for R249S by restriction fragment length polymorphisms, and both of them were controls. Of the 249 subjects tested for aflatoxin-albumin adducts, 168 (67%) were positive, with equal distribution between cases and controls. Aflatoxin-albumin adduct levels were low in the study, suggesting an overall low ongoing exposure to aflatoxin in this cohort. The R249S mutation was detected in 11 of 18 (61%) available tumor tissues. To assess whether low levels of mutant DNA were detectable in pre-diagnosis plasma, 14 plasma specimens from these patients were analyzed by short oligonucleotide mass analysis. Nine of them (64%) were found to be positive. Overall, these results suggest that HCC containing R249S can occur in the absence of significant recent exposure to aflatoxins. The use of short oligonucleotide mass analysis in the context of low ongoing aflatoxin exposure may allow the detection of R249S in plasma several months ahead of clinical diagnosis.

Wild CP. · Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, UK. · Food Nutr Bull. · Pubmed #17658084 No free full text.

Abstract: BACKGROUND: Aflatoxins are common contaminants of staple foods in sub-Saharan Africa. These toxins are human liver carcinogens, especially in combination with chronic infection with hepatitis B virus. However, in an agricultural setting, the effects on growth, immune status, and susceptibility to infectious disease in farm animals are also well recognized. These latter effects have been far less explored in human populations. OBJECTIVES: To review some of the more recent work on aflatoxins where the health outcomes seen in the agricultural setting, including growth impairment and immune suppression, have been investigated in human populations. The paper draws largely on examples from West Africa. The paper also sets out how knowledge gained about aflatoxins in the agricultural setting can be used to design intervention studies in human populations. METHODS: A review of the relevant literature. RESULTS: Human exposure to aflatoxins begins early in life, and recent studies in West Africa have demonstrated an association between exposure and growth faltering, particularly stunting, in young children. At present the underlying mechanisms for the latter effects are unknown but may include impairment of immunity and increased susceptibility to infections. Simple postharvest intervention strategies were successful in reducing aflatoxin exposure in a subsistence farm setting, providing a rationale for prevention of aflatoxin-related disease. CONCLUSIONS: There are potential benefits to public health from intervention strategies combining expertise in the agricultural and health settings to address the aflatoxin problem.

Turner PC, Sylla A, Kuang SY, Marchant CL, Diallo MS, Hall AJ, Groopman JD, Wild CP. · Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom LS2 9JT. · Cancer Epidemiol Biomarkers Prev. · Pubmed #16103461 links to  free full text

Abstract: Infection with hepatitis viruses and chronic exposure to high levels of dietary aflatoxins are the major etiologic agents for hepatocellular carcinoma in west Africa. A challenge for the prevention of hepatocellular carcinoma in this region is that both hepatitis B virus and aflatoxin exposures start early in life; indeed, aflatoxin exposures can start in utero and continue unabated throughout childhood. A mutation in the TP53 tumor suppressor gene at codon 249 (TP53 Ser249 mutation) has been reported previously for hepatocellular carcinoma tumors and matched plasma DNA samples in individuals from areas with high aflatoxin exposure. We examined whether the TP53 Ser249 mutation could be observed in DNA found in plasma of young children (ages 2-5 years) from Guinea, west Africa, a region of high aflatoxin exposure. Plasma aflatoxin-albumin adducts were present in 119 of 124 (96%) of the children, geometric mean of positives 9.9 pg/mg albumin (95% confidence interval, 8.8-11.0 pg/mg). This is the level and prevalence of exposure observed previously in adults. Following PCR amplification of plasma-derived DNA and detection using mass spectrometry, none of the samples were found to contain the TP53 Ser249 mutation. Because approximately 50% of the hepatocellular carcinomas in adults in west Africa have this specific TP53 Ser249 mutation, a lack of detection in samples from children ages <5 years may indicate that a window of opportunity for intervention exists that could be exploited to lower hepatocellular carcinoma risk.

Kirk GD, Turner PC, Gong Y, Lesi OA, Mendy M, Goedert JJ, Hall AJ, Whittle H, Hainaut P, Montesano R, Wild CP. · Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/Department of Health and Human Services, Bethesda, MD 20892, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #15734960 links to  free full text

Abstract: High rates of hepatocellular carcinoma (HCC) in The Gambia, West Africa, are primarily due to a high prevalence of chronic hepatitis B virus infection and heavy aflatoxin exposure via groundnut consumption. We investigated genetic polymorphisms in carcinogen-metabolizing (GSTM1, GSTT1, HYL1*2) and DNA repair (XRCC1) enzymes in a hospital-based case-control study. Incident HCC cases (n = 216) were compared with frequency-matched controls (n = 408) with no clinically apparent liver disease. Although the prevalence of variant genotypes was generally low, in multivariable analysis (adjusting for demographic factors, hepatitis B virus, hepatitis C virus, and TP53 status), the GSTM1-null genotype [odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.21-4.95] and the heterozygote XRCC1-399 AG genotype (OR, 3.18; 95% CI, 1.35-7.51) were significantly associated with HCC. A weak association of the HYL1*2 polymorphism with HCC was observed but did not reach statistical significance. GSTT1 was not associated with HCC. The risk for HCC with null GSTM1 was most prominent among those with the highest groundnut consumption (OR, 4.67; 95% CI, 1.45-15.1) and was not evident among those with less than the mean groundnut intake (OR, 0.64; 95% CI, 0.20-2.02). Among participants who had all three suspected aflatoxin-related high-risk genotypes [GSTM1 null, HLY1*2 (HY/HH), and XRCC1 (AG/GG)], a significant 15-fold increased risk of HCC was observed albeit with imprecise estimates (OR, 14.7; 95% CI, 1.27-169). Our findings suggest that genetic modulation of carcinogen metabolism and DNA repair can alter susceptibility to HCC and that these effects may be modified by environmental factors.

Wojnowski L, Turner PC, Pedersen B, Hustert E, Brockmöller J, Mendy M, Whittle HC, Kirk G, Wild CP. · Department of Pharmacology, University Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany. · Pharmacogenetics. · Pubmed #15454734 No free full text.

Abstract: OBJECTIVES: Major risk factors for hepatocellular carcinoma (HCC) are hepatitis viruses and exposure to aflatoxins, including aflatoxin B1 (AFB1). The mutagenic effect of AFB1 results from hepatic bioactivation to AFB1-exo-8,9-epoxide. This is in part catalysed by CYP3A5, an enzyme expressed polymorphically. We investigated the role of CYP3A5 polymorphisms in the formation of AFB1-exo-8,9-epoxide in The Gambia, a population exposed to high aflatoxin levels. METHODS: Common CYP3A5 polymorphisms were identified in an African-American population. Subsequently, 288 Gambian subjects were genotyped and CYP3A5 activity predicted using haplotypes of the three variant loci (CYP3A5*3, *6 and *7) associated with decreases in protein expression. CYP3A5 expression was then compared to aflatoxin-albumin (AF-alb) adduct, a biomarker of AFB1 bioactivation; data were also analysed in relation to expression of other aflatoxin-metabolizing enzymes. RESULTS: CYP3A5 haplotypes reflecting high CYP3A5 protein expression were associated with increased AF-alb. Compared to individuals with predicted low expression those predicted to express CYP3A5 from one allele displayed 16.1% higher AF-alb (95% CI: -2.5, 38.2, P = 0.093) and homozygous expressers displayed 23.2% higher AF-alb levels (95% CI: -0.01, 52.0, P = 0.051). The effect of the CYP3A5 polymorphism was strongest in individuals with low CYP3A4 activity with a 70.1% increase in AF-alb (95% CI: 11.8, 158.7, P < 0.05) in high compared to low expressers. A similar effect was observed for individuals with null alleles of GSTM1, which conjugates the AFB1-exo-8,9-epoxide to reduced glutathione. CONCLUSIONS: The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1-exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC.

Barraud L, Douki T, Guerret S, Chevallier M, Jamard C, Trepo C, Wild CP, Cadet J, Cova L. · INSERM U271, Grenoble, France. · Cancer Detect Prev. · Pubmed #11341355 No free full text.

Abstract: The aim of our study was to use the Pekin duck model to investigate the interactions between hepadnaviral infection and aflatoxin B1 (AFB1) exposure including the role of both factors in the induction of oxidative stress in the liver. AFB1 exposure of duck hepatitis B virus (DHBV) infected Pekin ducks induced a significant increase in viral replication associated with an intense biliary ductular cells proliferation. Interestingly, extremely high levels of AFB1-DNA adducts (40-120 pmol AFB1-Fapy/mg DNA) and AFB1-albumin adducts (1,500-3,000 pg AFB1-lys Eq/mg albumin) were detected in duck liver and serum respectively, as compared to other animal species exposed to a similar AFB1 dose. DHBV infection was found to induce a non-significant increase in AFB1-albumin adduct levels in duck serum. During the treatment duration there was no effect on formation of oxidative base damage within DNA and no effect on oxidative lipid peroxidation following either viral infection or AFB1 exposure. In terms of hepatic antioxidant enzymes (catalase, superoxide dismutase (SOD), glutathione peroxidase) a significant increase in SOD activity occurred following AFB1 exposure, but not DHBV infection, but this was observed only after the cessation of treatment, when biliary ductular cells proliferation was reduced.

Turner PC, Mendy M, Whittle H, Fortuin M, Hall AJ, Wild CP. · Molecular Epidemiology Unit, University of Leeds, Leeds, UK. · Trop Med Int Health. · Pubmed #11169271 links to  free full text

Abstract: OBJECTIVES: To examine the relationship between hepatitis B virus (HBV) infection and biomarkers of aflatoxin exposure in West African children. METHODS: Sera from 444 children aged 3-4 years who were selected to be representative of their communities were analysed for aflatoxin-albumin (AF-alb) adducts and markers of hepatitis B infection. RESULTS: There was large interindividual variation in adduct levels (range: 2.2 to 459 pg AF-lysine eq./mg albumin). Adduct level was strongly correlated with season, with an approximately twofold higher mean level in the dry season than the wet. Geometric mean adduct levels in uninfected children, chronic carriers and acutely infected children were 31.6 (n = 404), 44.9 (n = 34) and 96.9 (n = 6) pg/mg, respectively. The relationship of AF-alb level to ethnicity, month of sampling and HBV status was examined in a multiple regression model. Month of obtaining the blood sample (P = 0.0001) and HBV status (P = 0.0023) each made a highly significant contribution to the model; the high AF-alb levels were particularly associated with acute infection. Elevated serum transaminase levels were significantly (P < 0.002) associated with HBV status, with acutely infected children having the highest levels. Ethnicity was not significantly associated with AF-alb adduct levels in the model (P = 0.09). CONCLUSIONS: HBV infection and month of sampling both significantly influence AF-alb adduct levels. The effect of seasonality on adducts was also observed in a previous study of 347 Gambian adults, although there was no correlation between adduct level and HBV status in that population. This difference between children and adults may reflect a more severe effect of HBV infection, particularly acute infection, in childhood on hepatic AF metabolism.

Wild CP, Yin F, Turner PC, Chemin I, Chapot B, Mendy M, Whittle H, Kirk GD, Hall AJ. · Molecular Epidemiology Unit, School of Medicine, University of Leeds, UK. · Int J Cancer. · Pubmed #10728587 No free full text.

Abstract: Aflatoxins together with chronic hepatitis B virus (HBV) infection contribute to the high incidence of hepatocellular carcinoma in developing countries. An understanding of the mechanism of interaction between these factors would provide a strong rationale for developing effective prevention strategies. In this study in The Gambia we examined the effect of environmental (place of residence and timing of sample collection) and host factors (age, sex, HBV status and interindividual variations in carcinogen metabolising enzymes) in determining blood aflatoxin-albumin adduct levels in 357 individuals of whom 181 were chronic HBV carriers. Samples were analysed for aflatoxin-albumin adducts, HBV status and genotypes of glutathione S-transferase (GST) M1, GSTT1, GSTP1 and epoxide hydrolase (EPXH). Urine samples were analysed for 6beta-hydroxycortisol:cortisol ratio as a marker of cytochrome P450 (CYP) 3A4 activity. Adduct levels were significantly higher in subjects resident in rural [geometric mean adduct level 34.9 pg aflatoxin B1-lysine equivalent (28.5-42.8; 95%CI)/mg albumin] than in periurban areas [22.2 pg (14.9-33.4)/mg] and were approximately twice as high in the dry season [mid-February to March; 83.2 pg (53.3-130.8)/mg] than the wet [July to August; 34.9 pg (28.5-42.8)/mg]. In contrast, HBV status, CYP3A4 phenotype, GSTT1, GSTP1 and EPXH genotypes were not associated with aflatoxin-albumin adduct level. However, mean adduct levels were significantly higher in non-HBV infected subjects with GSTM1 null genotype. The main factors which affect aflatoxin-albumin adduct levels in this population are environmental, notably place of residence and timing of sample collection. This study further emphasises the priority to reduce aflatoxin exposure in these communities by primary prevention measures.

Chemin I, Ohgaki H, Chisari FV, Wild CP. · Unit of Environmental Carcinogenesis, International Agency for Research on Cancer, Lyon, France. · Liver. · Pubmed #10220736 No free full text.

Abstract: AIMS/BACKGROUND: The objective of this work was to evaluate the possible modulation of carcinogen metabolizing enzymes in relation to chronic infection by hepatitis B virus (HBV). This was to test whether enzyme level is altered in association with HBV gene expression per se or only when that expression was associated with an induction of liver injury. METHODS: For this purpose, we studied four different HBV transgenic mouse lineages (23.3, 45.2, 50.4 and 107.5) that express the transgene encoding for the large envelope protein (HBsAg) at different levels. These lineages exhibit an associated liver injury which progresses with age and is positively correlated with the degree of accumulation of HBsAg in the hepatocytes. The modulation of levels of cytochrome P450 (1a, 2a-5, 2b, 2c, 3A4 and 2E1) and glutathione S-transferases (GST alpha and pi) involved in carcinogen metabolism was examined by immunohistochemistry in these lineages. RESULTS: While we observed an increase in staining intensity of P450s 1-a and 2a-5 in lineages expressing cytopathic amounts of HBsAg (lineages 50.4 and 45.2), we only observed minor changes or no changes at all for the other lineages (23.3 and 107.5). Staining with antibodies to cytosolic pi class GST demonstrated an increase in older mice, although no major alterations were observed for GST alpha. CONCLUSIONS: These results suggest that liver cell injury induced by accumulation of HBV antigens can result in the induction of some carcinogen metabolizing enzymes and this may be one mechanism of chemical-viral interaction in hepatocarcinogenesis.

Barraud L, Guerret S, Chevallier M, Borel C, Jamard C, Trepo C, Wild CP, Cova L. · INSERM U271, Lyon, France. · Hepatology. · Pubmed #10094981 No free full text.

Abstract: Epidemiological studies have suggested synergistic interactions between chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure in the etiology of hepatocellular carcinoma (HCC), although the molecular mechanisms of their interactions are still not understood. The aim of this study was to use the Pekin duck model to investigate the impact of AFB1 exposure on duck hepatitis B virus (DHBV) replication during the early stages of virus-carcinogen interactions. Six-week-old chronic DHBV-carrier or uninfected ducks were exposed to AFB1 for 5 weeks or treated with dimethylsulfoxide (DMSO) as a control. Animals were observed for 6 to 13 weeks after AFB1 treatment to study the influence of AFB1 exposure on DHBV replication and liver pathologies. Histological analysis showed more marked changes in the livers of AFB1-treated ducks, and these were enhanced by DHBV infection. A significant increase in serum and liver DHBV DNA level was observed in AFB1-treated ducks as compared with DMSO-treated controls. In addition, viral RNAs, in particular the pregenomic RNA that is the template of viral replication, and intrahepatic DHBV DNA replicative intermediates, were significantly increased by AFB1 treatment. Moreover, an overexpression and accumulation of DHBV large envelope (L) protein was observed in the hepatocytes of AFB1-exposed animals. The in vitro study has further confirmed an increase in intracellular viral DNA and in virus release in AFB1-treated primary duck hepatocytes. Taken together, our results indicate that AFB1 exposure leads to an increase in virus gene expression associated with intrahepatic accumulation of DHBV L protein and enhanced liver pathology.