Hypersensitivity of xeroderma pigmentosum cells to dietary carcinogens.
Xeroderma pigmentosum patients, in addition to ultraviolet-induced skin cancers, have an increased prevalence of neoplasms occurring in sites shielded from ultraviolet radiation. We postulated that these internal neoplasms might be related to ingestion of dietary carcinogens. As model dietary carcinogens, we studied the tryptophan pyrolysis products, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). These dietary compounds bind to DNA and are highly mutagenic and carcinogenic. Cytotoxicity of these compounds was examined in cultured lymphoblastoid cell lines from xeroderma pigmentosum patients in complementation groups A, B, C, D and E and the variant form and from normal donors. All xeroderma pigmentosum lymphoblastoid cell lines showed a greater reduction in viable cell concentration than the 2 normal lymphoblastoid cell lines following addition of Trp-P-1 or Trp-P-2 (5 micrograms/ml) to the culture medium. Possible differences in cellular activation of these compounds were overcome by treating the cells with rat-liver microsome-activated Trp-P-2. There was a greater reduction in viable cell concentration in the xeroderma pigmentosum group A and D cells than in the normal lymphoblastoid cell lines after treatment with activated Trp-P-2. These data suggest that the xeroderma pigmentosum DNA-repair system is defective in repairing Trp-P-1 and Trp-P-2 induced DNA damage in addition to being defective in repairing ultraviolet-induced DNA damage. Thus xeroderma pigmentosum patients may be at increased risk of toxicity from some dietary carcinogens.
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002243:Carbolines / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004032:Diet; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D008214:Lymphocytes; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000633:toxicity; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D002243:Carbolines; D002273:Carcinogens; D007211:Indoles; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D014364:Tryptophan; D001189:Aryl Hydrocarbon Hydroxylases; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole