Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer
Malik DE, David RM, Gooderham NJ
Archives of toxicology · 12 citas
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Publicación
- Publicado
- 2018-01-23 · Arch Toxicol · vol. 92 · número 4 · págs. 1639–1655
- Editorial
- Springer Science+Business Media
- Citado
- 17 citas · más que el 61% de estudios similares · 0.7× el promedio de su campo
- Referencias
- 92 trabajos
- Acceso
- Acceso abierto (revista híbrida) · CC-BY
- Áreas de investigación
- Carcinogens and Genotoxicity Assessment · Effects and risks of endocrine disrupting chemicals · Nutritional Studies and Diet
- Palabras clave
- Genotoxicity, Chemistry, Carcinogen, Estrogen receptor, Aryl hydrocarbon receptor, Micronucleus test, Toxicity, Oxidative stress, Pharmacology, DNA damage, CYP1B1, Mammary tumor, Comet assay, Biochemistry, Internal medicine, Breast cancer, Cytochrome P450, Cancer, Metabolism, Biology, Medicine, DNA
- MeSH
- humans, breast neoplasms, dna damage, reactive oxygen species, ethanol, imidazoles, cytochrome p-450 cyp2e1, estrogen receptor alpha, carcinogens, life style, oxidative stress, female, mcf-7 cells, cytochrome p-450 cyp1b1, red meat
3 autores
- Durr-e-shahwar Malik🇬🇧Imperial College London
- Rhiannon M. David🇬🇧🇸🇬🇵🇱AstraZeneca (United Kingdom); AstraZeneca (Singapore); AstraZeneca (Poland); Imperial College London
- Nigel J. Gooderham🇬🇧 · autor de correspondenciaImperial College London
Resumen
El texto original del estudio, en el idioma en que se publicó.
Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10-7-10-4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10-3-10-1 M) with PhIP (10-7-10-4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.
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