tim333
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- Feb 27, 2020
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Alcohol and Tobacco Smoke in Retinoid Metabolism and Signaling: Implications for Carcinogenesis
Abstract
Considerable evidence demonstrates that retinoids (retinol, retinoic acid, and retinyl ester, which are also the important metabolites from provitamin A carotenoids), may be effective in the prevention and treatment of a variety of human chronic diseases, including cancer. Substantial work has been done investigating the mechanisms by which tobacco smoke and excessive alcohol intake interfere with retinoid metabolism and signaling. Exposure to cigarette smoke subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A. Further, oxidative stress can result in cleavage of Β-carotene at positions other than the central double bond, decreasing the production of retinoic acid from this vitamin A precursor. This leads to aberrant retinoid signaling through nuclear retinoid receptors, while at the same time cigarette smoke also causes dysregulated signaling through the mitogen-activated protein kinase signaling pathways. Alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases, induces cytochrome P450 enzymes (particularly CYP2E1) that degrade retinol and retinoic acid, and alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. Moreover, this alcohol-impaired retinoid homeostasis interferes with retinoic acid signaling by decreasing target gene expression and interfering with retinoic acid cross-talk with the mitogen-activated protein kinase pathways. The overall effect of both cigarette smoke and chronic, excessive alcohol intake is dysregulated apoptosis and uncontrolled cellular proliferation, which can act to promote the process of carcinogenesis. Nutritional interventions that serve to restore normal retinoid signaling and functioning may offer protection at the cellular level and represent a means to modify cancer risk in high-risk human populations.
Abstract
Considerable evidence demonstrates that retinoids (retinol, retinoic acid, and retinyl ester, which are also the important metabolites from provitamin A carotenoids), may be effective in the prevention and treatment of a variety of human chronic diseases, including cancer. Substantial work has been done investigating the mechanisms by which tobacco smoke and excessive alcohol intake interfere with retinoid metabolism and signaling. Exposure to cigarette smoke subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A. Further, oxidative stress can result in cleavage of Β-carotene at positions other than the central double bond, decreasing the production of retinoic acid from this vitamin A precursor. This leads to aberrant retinoid signaling through nuclear retinoid receptors, while at the same time cigarette smoke also causes dysregulated signaling through the mitogen-activated protein kinase signaling pathways. Alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases, induces cytochrome P450 enzymes (particularly CYP2E1) that degrade retinol and retinoic acid, and alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. Moreover, this alcohol-impaired retinoid homeostasis interferes with retinoic acid signaling by decreasing target gene expression and interfering with retinoic acid cross-talk with the mitogen-activated protein kinase pathways. The overall effect of both cigarette smoke and chronic, excessive alcohol intake is dysregulated apoptosis and uncontrolled cellular proliferation, which can act to promote the process of carcinogenesis. Nutritional interventions that serve to restore normal retinoid signaling and functioning may offer protection at the cellular level and represent a means to modify cancer risk in high-risk human populations.