Activation of aflatoxin B1 by expression of human CYP1A2 polymorphisms in Saccharomyces cerevisiae.

Fasullo, Michael; Smith, Autumn; Egner, Patricia; Cera, Cinzia

Fasullo, Michael; Smith, Autumn; Egner, Patricia; Cera, Cinzia.

Afiliación

Fasullo M; Ordway Research Institute, Center for Medical Sciences, 150 New Scotland Avenue, Albany, NY 12209, USA; Department of Biomedical Sciences, School of Public Health, Center for Medical Sciences, 150 New Scotland Avenue, Albany NY, USA. Electronic address: mfasullo@albany.edu.
Smith A; Ordway Research Institute, Center for Medical Sciences, 150 New Scotland Avenue, Albany, NY 12209, USA.
Egner P; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Cera C; Ordway Research Institute, Center for Medical Sciences, 150 New Scotland Avenue, Albany, NY 12209, USA.

Mutat Res Genet Toxicol Environ Mutagen ; 761: 18-26, 2014 Feb.

Article en En | MEDLINE | ID: mdl-24472830

RESUMEN

Human susceptibility to environmental carcinogens is highly variable and depends on multiple genetic factors, including polymorphisms in cytochrome P450 genes. Although epidemiological studies have identified individual polymorphisms in cytochrome P450 genes that may alter cancer risk, there is often conflicting data about whether such polymorphisms alter the genotoxicity of environmental carcinogens. This is particularly true of the CYP1A2 polymorphisms that confer differential activation of multiple human carcinogens. To determine whether a single cytochrome P450 polymorphism confers higher levels of carcinogen-associated genotoxicity, we chose an organism that lack enzymes to metabolically activate aflatoxins and expressed individual human P450 genes in budding yeast. We measured the frequencies of recombination, Rad51 foci formation, 7-methoxyresorufin O-demethylase activities, and the concentrations of carcinogen-associated DNA adducts in DNA repair proficient yeast expressing P450 polymorphisms after exposure to aflatoxin B1 (AFB1).We measured growth of rad4 rad51 cells expressing CYP1A2 polymorphisms while exposed to AFB1. We observed that there was significantly less AFB1-associated genotoxicity in yeast expressing CYP1A2 I386F, while yeast expressing CYP1A2 C406Y exhibited intermediate levels of genotoxicity compared to yeast expressing CYP1A2 D348N or wild type. We conclude that differences in carcinogen genotoxicity can be observed in yeast expressing different CYP1A2 alleles. This is the first report that carcinogen-associated P450 polymorphisms can be studied in yeast.

Asunto(s)

Aflatoxina B1/toxicidad; Carcinógenos/toxicidad; Citocromo P-450 CYP1A2/genética; Citocromo P-450 CYP1A2/metabolismo; Saccharomyces cerevisiae/enzimología; Aflatoxina B1/metabolismo; Sustitución de Aminoácidos; Carcinógenos/metabolismo; Aductos de ADN/metabolismo; Proteínas de Unión al ADN/genética; Regulación Enzimológica de la Expresión Génica; Regulación Fúngica de la Expresión Génica; Humanos; Organismos Modificados Genéticamente; Polimorfismo Genético; Recombinasa Rad51/genética; Recombinación Genética/efectos de los fármacos; Saccharomyces cerevisiae/genética; Proteínas de Saccharomyces cerevisiae/genética

Palabras clave

Aflatoxin B(1); Budding yeast; Cytochrome P450

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Carcinógenos / Aflatoxina B1 / Citocromo P-450 CYP1A2 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mutat Res Genet Toxicol Environ Mutagen Año: 2014 Tipo del documento: Article Pais de publicación: Países Bajos

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