Suseptibilidad Individual a Los Efectos Del Alcohol

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ANN IST SUPER SANITÀ 2006 | VOL. 42, NO. 1: 8-16

RESEARCH FROM ANIMAL TESTING TO CLINICAL EXPERIENCE

Individual susceptibility and alcohol effects: biochemical and genetic aspects
Simonetta Gemma, Susanna Vichi and Emanuela Testai Dipartimento di Ambiente e Connessa Prevenzione Primaria, Istituto Superiore di Sanità, Rome, Italy
Summary. The large interethnic and interindividualvariability in alcohol-induced toxic effects comes from a combination of genetic and environmental factors, influencing ethanol toxicokinetics. The hepatic enzymatic systems involved in ethanol metabolism are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and microsomal P4502E1 (CYP2E1). ADH oxidizes ethanol to acetaldehyde, which is very efficiently oxidized to acetate by ALDH. About 10%of moderate quantities of ethanol is metabolised by CYP2E1; the percentage increases when ADH is saturated. During ethanol metabolism reactive oxygen species and hydroxyethyl radicals are generated, causing oxidative stress, responsible for most ethanol-induced liver damage. For their critical role in detoxifying radicals, glutathione S-transferase are gaining attention in the etiology ofalcoholism. All these enzymes have been shown to be polymorphic, giving rise to altered phenotypes. For this reason recent studies have looked for a correlation between metabolic variability and differences in alcohol abuse-related effects.
Key words: ethanol, interindividual variability, polymorphism, alcohol dehydrogenase, aldehyde dehydrogenase, CYP2E1, glutathione S-transferase.

Riassunto(Variabilità individuale ed effetti dell’alcol: aspetti biochimici e genetici). L’ampia variabilità interetnica ed interindividuale degli effetti tossici dovuti all’alcol deriva da una combinazione di fattori genetici ed ambientali che influenzano la tossicocinetica dell’etanolo. I sistemi enzimatici epatici coinvolti nel metabolismo dell’etanolo sono l’alcol deidrogenasi (ADH), l’aldeide deidrogenasi(ALDH) e il citocromo P450 2E1 (CYP2E1). L’ADH ossida l’etanolo ad acetaldeide che è efficientemente biotrasformata ad acetato dalla ALDH. Circa il 10% di moderate quantità di etanolo viene metabolizzato dal CYP2E1; la percentuale aumenta quando l’ADH è saturata. Durante il metabolismo dell’etanolo si generano specie reattive dell’ossigeno e radicali idrossietilici che causano stress ossidativo,principale responsabile del danno epatico indotto da etanolo. A causa del ruolo critico delle glutatione S-transferasi nella detossificazione dei radicali, il loro coinvolgimento nell’eziologia dell’alcolismo sta ricevendo crescente attenzione. Tutti questi enzimi sono presenti come forme polimorfiche che possono originare fenotipi alterati. Per questa ragione studi recenti hanno cercato unacorrelazione fra variabilità metabolica e differenze negli effetti dell’abuso di alcol.
Parole chiave: etanolo, variabilità interindividuale, polimorfismo, alcol deidrogenasi, aldeide deidrogenasi, CYP2E1, glutatione S-transferasi.

INTRODUCTION Alcoholism is a common disorder with a complex origin and outcome, since individuals react differently when exposed to comparable amounts of alcohol. Manyepidemiological, biomedical and psychosocial studies support the hypothesis that some individuals suffer more severe adverse effects following alcohol use. Physiological features (such as age and gender) and socio-cultural/psychological factors may play a relevant role in determining the huge interindividual variability in the thresholds and lifetime prevalence of this disease. Indeed, socialrestrictions have been shown to have a huge influence on the risk for alcohol dependence, particularly in societies with a high prevalence of alcoholism [1]. Excessive and prolonged use of alcoholic beverages is the cause of serious social

and medical disorders in a significant number of individuals associated with socioeconomic consequences for the rest of the population. Alcohol related pathologies...