title: Determination of human exposure to the dietary carcinogen 3-amino-1, 4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) from hemoglobin adduct: the relationship to DNA adducts.
abstract: A quantitative method for estimation of the exposure of the food-borne carcinogen, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), was developed by the analysis of its hemoglobin binding in rats. This method was then applied to show the presence of Trp-P-1-hemoglobin adducts in human blood. In rat experiments, 0.2 and 0.07% of the administered [14C]Trp-P-1 formed stable covalent adducts with blood hemoglobin and plasma proteins respectively. Subsequent strong acidic treatment (6 N HCl, 110 degrees C, 24 h) of the Trp-P-1-hemoglobin adducts cleaved peptide bonds of globin, and yielded mainly three derivatives of Trp-P-1. One of them (TPHB) represented approximately 50% of the total Trp-P-1-hemoglobin adducts and was suitable for detection through its strong fluorescence. TPHB was used as a surrogate marker of the Trp-P-1-hemoglobin adducts. Linear dose dependency of Trp-P-1 binding to liver DNA and hemoglobin in rats was confirmed by 32P-postlabeling analysis and TPHB assay. The absence of Trp-P-1-DNA adducts and TPHB in nontreated rats was also confirmed. Using TPHB as a tool for human dosimetry of Trp-P-1, human blood samples from four healthy individuals were examined. TPHB was detected in all samples ranging from 0.23 to 4.33 pmol/g hemoglobin. These results suggest human exposure to Trp-P-1, probably from cooked foods or cigarette smoke, and its possible relationship to human carcinogenesis.
authors.affiliation: Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Umemoto
authors.forename: Y
authors.initials: Y
authors.lastname: Monden
authors.forename: S
authors.initials: S
authors.lastname: Grivas
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: T
authors.initials: T
authors.lastname: Sugimura
mesh_terms: D000328:Adult; D000818:Animals; D002243:Carbolines / Q000032:analysis* / Q000378:metabolism; D002273:Carcinogens / Q000032:analysis* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000032:analysis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005260:Female; D005506:Food Contamination; D006454:Hemoglobins / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002243:Carbolines; D002273:Carcinogens; D006454:Hemoglobins; D004247:DNA; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole