2-3-dihydro-2-(n(7)-guanyl)-3-hydroxyaflatoxin-b1 and Hepatitis-B

Chemical-specific markers have been developed for a number of environmental carcinogens for use as molecular dosimeters of individual exposure. In addition to contributing substantially to the specificity and sensitivity of epidemiological studies aimed at determining the role of environmental agents in the etiology of human cancers, some of these biomarkers may prove to be useful endpoints for assessing the efficacy of preventive interventions including exposure avoidance or remediation and chemoprevention. Biomarkers of the biologically effective dose may be particularly useful in this context in that they provide a mechanistic linkage between exposure and disease outcome. The biologically effective dose reflects the amount of toxicant that has interacted with its critical molecular target and can be measured through a variety of analytical techniques as either carcinogen-DNA or -protein adducts. Approaches for the development and validation of aflatoxin adduct biomarkers are presented as a paradigm for the application of carcinogen-specific markers for cohort selection and as modifiable endpoints for assessing efficacy in chemoprevention trials.

Topics: Aflatoxin B1; Aflatoxins; Aged; Anticarcinogenic Agents; Biomarkers, Tumor; Carcinogens; Clinical Trials as Topic; Cohort Studies; DNA Adducts; Guanine; Hepatitis B; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Proteins; Pyrazines; Risk Factors; Thiones; Thiophenes

Our study was designed to assess the fecal and urinary excretion of 3 aflatoxin B1 (AFB1) metabolites, aflatoxins M1 (AFM1) and Q1 (AFQ1) and aflatoxin B1-N7-guanine (AFB-N7-guanine) that are produced by the predominant forms of cytochrome P450 enzymes responsible for the biotransformation of AFB1. Fecal and urinary AFM1, AFQ1 and urinary AFB-N7-guanine were assessed in 83 young Chinese males selected from a larger population (n = 300) based on detectable urinary AFM1. The concentration of fecal AFQ1 (median 137 ng/g fresh weight, IQR 9.1 to 450) was approximately 60 times higher than that of AFM1 (2.3 ng/g, IQR 0.0 to 7.3). In urine, the median AFQ1 was 10.4 ng/ml (IQR 3.4 to 23.3), and the median AFM1 and AFB-N7-guanine 0.04 ng/ml (IQR 0.01 to 0.33) and 0.38 ng/ml (IQR 0.0 to 2.15), respectively. A subgroup (n = 14) with hepatitis B virus (HBV) infection had significantly higher fecal concentrations of AFQ1 (p = 0.043) and AFM1 (p = 0.001) than those who were hepatitis B-virus antigen (HBsAg) negative, and the respective differences in urinary AFQ1 and AFM1 concentrations approached statistical significance (p = 0.054, p = 0.138). Our study demonstrates that AFQ1 is excreted in urine and feces at higher levels than AFM1, and feces are an important route of excretion of these AFB1 metabolites. AFQ1 should be further assessed for its predictive value as a marker for exposure and risk of dietary aflatoxins.

Topics: Aflatoxin B1; Aflatoxin M1; Aflatoxins; China; Feces; Guanine; Hepatitis B; Humans; Male

Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is associated with an increased risk of hepatocellular carcinoma (HCC). The hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular DNA. To determine whether nutritional factors and hormonal status may influence the binding of AFB1 to hepatic DNA, a cross-sectional study was performed on a total of 42 male asymptomatic hepatitis B surface antigen (HBsAg) carriers and 43 male non-carriers in a cohort study on the multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo, AFB1-N7-guanine, was measured by high-performance liquid chromatography in urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg carriers had a higher detection rate of urinary AFB1-DNA adducts than non-carriers and the difference was statistically significant after multivariate adjustment. After taking into account the total AFB1 urinary metabolite level, chronic HBsAg carrier status, and other potential confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and beta-carotene were positively associated with the detection rate of the AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level was inversely related to the presence of the adducts in urine. The association of urinary AFB1-DNA adducts with the plasma levels of cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was observed at both low and high exposure levels of AFB1. There was a synergistic interaction of plasma alpha-tocopherol with alpha- and beta-carotene on the adduct levels. No association with the adducts was found for plasma levels of retinol and testosterone. This study demonstrated different associations of antioxidant vitamins with AFB1-DNA adduct formation. The data consistent with our previous finding in cultured woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced AFB1-DNA adduct formation suggest that prospective investigation of the relationship between plasma micronutrients and risk of AFB1-related HCC is warranted.

Topics: Adult; Aflatoxin B1; Aged; Antioxidants; beta Carotene; Carotenoids; Chronic Disease; DNA; DNA Adducts; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Testosterone; Vitamin E; Vitamins

Covalent binding of aflatoxin B1 (AFB1) with hepatic DNA may be a critical step in hepatocarcinogenesis. The extent of the AFB1 binding to DNA may depend on various endogenous factors and concurrent exposure to other environmental agents. This study was performed to determine whether any individual characteristics correlated with the formation of AFB1-DNA adducts. The major AFB1-DNA adduct, AFB1-N7-guanine, was measured using a high performance liquid chromatographic assay in urine samples from 43 asymptomatic hepatitis B virus surface antigen carriers and 43 noncarriers randomly selected from a cohort study in Taiwan. The total aflatoxin metabolite level was associated with the detection rate of urinary AFB1-N7-guanine adducts in a dose-dependent manner. The AFB1-DNA adduct excreted in the urine was detectable in 60% of individuals who smoked cigarettes but abstained from alcohol, 64% of individuals who had a habit of drinking alcohol but not smoking cigarettes, and only 29% of those who neither smoked nor drank alcohol. The association between urinary AFB1-DNA adduct level and habits of smoking cigarettes and drinking alcohol remained statistically significant when adjustment was made for potential confounders. There was a significant increase with age for the detection rate of urinary AFB1-N7-guanine adducts. Age and habits of cigarette smoking and alcohol drinking were also found to be associated with a higher percentage of AFB1-N7-guanine in total AFB1 metabolite excretion, indicating an increased activation of AFB1. No significant association with the AFB1-DNA adduct level was observed for hepatitis B virus surface antigen carrier status, educational level, and ethnicity. These data suggest a potential role of age, cigarette smoking, and alcohol drinking in AFB1-induced hepatocarcinogenesis.

Topics: Aflatoxin B1; Age Factors; Alcohol Drinking; Biomarkers; Carcinogens; Carcinoma, Hepatocellular; Carrier State; DNA Adducts; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Humans; Liver Neoplasms; Logistic Models; Male; Multivariate Analysis; Prospective Studies; Risk Factors; Smoking; Taiwan

Two major etiological agents, hepatitis B virus and aflatoxin B1, are considered to be involved in the induction of liver cancer in Africa. In order to elucidate any synergistic effect of these two agents we conducted a study in various parts of Kenya with different liver cancer incidence in order to establish the rate of exposure to aflatoxin and the prevalence of hepatitis infections. Of all tested individuals 12.6% were positive for aflatoxin exposure as indicated by the urinary excretion of aflatoxin B1-guanine. Assuming no annual and seasonal variation, a regional variation in the exposure was observed. The highest rate of aflatoxin exposure was found in the Western Highlands and Central Province. The incidence of hepatitis infection nationwide as measured by the presence of the surface antigens was 10.6%, but a wide regional variation was observed. A multiplicative and additive regression analysis to investigate if hepatitis and aflatoxin exposure had a synergetic effect in the induction of liver cancer was negative. However, a moderate degree of correlation between the exposure to aflatoxin and liver cancer was observed when the study was limited to certain ethnic groups. The study gives additional support to the hypothesis that aflatoxin is a human liver carcinogen.

Topics: Aflatoxin B1; Aflatoxins; Carcinoma, Hepatocellular; DNA Damage; Female; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Humans; Kenya; Liver Neoplasms; Male; Sex Factors