Leandro Néstor Quintans

Oxidation of ethanol to acetaldehyde and free radicals by rat testicular microsomes

A large number of epidemiological studies evidencing that excessive alcohol consumption is associated with impaired testosterone production and testicular atrophy are available in the literature. One hypothesis to explain the deleterious action of alcohol involves the in situ biotransformation to acetaldehyde, but it strongly suggests the need to learn more about the enzymatic processes governing alcohol metabolism to acetaldehyde in different cellular fractions since limited information is available in the literature. In this article we report studies on the metabolic conversion of alcohol to acetaldehyde and to 1-hydroxyethyl radicals in rat testicular microsomal fractions. The oxidation of ethanol to acetaldehyde in rat testes microsomal fraction was mostly of enzymatic nature and strongly dependent on the presence of NADPH and oxygen. Several compounds were able to significantly decrease the production of acetaldehyde: SKF 525A; diethyldithiocarbamate; esculetin; gossypol; curcumin; quercetin; dapsone; and diphenyleneiodonium. Microsomal preparations in the presence of NADPH were also able to produce both hydroxyl and 1-hydroxyethyl free radicals. Their generation was modulated by the presence of diphenyleneiodonium, gossypol, and deferoxamine. Results show that rat microsomal fractions are able to metabolize alcohol to deleterious chemicals, such as acetaldehyde and free radicals, that may be involved in ethanol toxic effects. Enzymes involved could include CYP2E1, P450 reductase, and other enzymes having lipoxygenase- /peroxidase-like behavior.

Preventive Effects of Plant Polyphenols in the Promotion of Mammary Cancer and Testicular Damage Induced by Alcohol Drinking

Excessive alcohol drinking promotes mammary cancer in women and deleterious effects to testes in males. Evidence about the need of ethanol bioactivation to acetaldehyde and promotion of oxidative stress on these harmful effects of alcohol drinking is reviewed. In situ relevant pathways of acetaldehyde formation exist in the microsomal and cytosolic fractions of mammary tissue which are accompanied of its poor detoxication and this lead to acetaldehyde accumulation. This accumulative process, the oxidative stress promoted, and the pro-estrogenic effects of alcohol might be involved in the carcinogenic action of alcohol drinking. Acetaldehyde formation and ethanol promoted oxidative stress also occurs in the cytosolic and microsomal fractions of the testes. In this chapter, the inhibitory effects of several polyphenols on these pathways of acetaldehyde formation in both tissues at very low concentrations were studied. These effects and the known antioxidant properties of plant polyphenols open the possibility for future preventive studies of both pathologies.

Acetaldehyde Content and Oxidative Stress in the Deleterious Effects of Alcohol Drinking on Rat Uterine Horn

After alcohol exposure through a standard Lieber and De Carli diet for 28 days, a severe atrophy in the rat uteirne horn was observed, accompanied by significant alterations in its epithelial cells. Microsomal pathway of acetaldehyde production was slightly increased. Hydroxyl radicals were detected in the cytosolic fraction, and this was attributed to participation of xanthine oxidoreductase. They were also observed in the microsomal fraction in the presence of NADPH generating system. No generation of 1-hydroxyethyl was evidenced. The t-butylhydroperoxide-induced chemiluminescence analysis of uterine horn homogenates revealed a significant increase in the chemiluminiscence emission due to ethanol exposure. In the animals repeatedly exposed to alcohol, sulfhydryl content from uterine horn proteins was decreased, but no significant changes were observed in the protein carbonyl content from the same samples. Minor but significant decreasing changes were observed in the GSH content accompanied by a tendency to decrease in the GSH/GSSG ratio. A highly significant finding was the diminished activity content of glutathione peroxidase. Results suggest that acetaldehyde accumulation plus the oxidative stress may play an additional effect to the alcohol-promoted hormonal changes in the uterus reported by others after chronic exposure to alcohol.

Radioprotective effect of ethyl pyruvate alone or as a coadyuvant of amifostine

Entre los radioprotectores con uso clínico se destaca la amifostina (WR2721), eficaz pero con efectos secundarios que impiden su uso repetitivo. Es interés de los autores desarrollar radioprotectores menos tóxicos, por sí mismos o como coadyuvantes de amifostina. Ratas machos o hembras se expusieron a una dosis de rayos X de 2 Gy. Se ensayó el piruvato de etilo, solo o conjuntamente con amifostina. Cuarenta y ocho horas después de la exposición a la radiación, se realizó el recuento de eritrocitos, de leucocitos y la fórmula leucocitaria. Los efectos genotóxicos se evaluaron en leucocitos de sangre mediante el ensayo Cometa. Se realizaron también estudios de supervivencia a 60 días post-irradiación. En los animales irradiados disminuyeron los eritrocitos, y el recuento de leucocitos se redujo drásticamente respecto al control, presentando además una fórmula alterada. El tratamiento con piruvato de etilo resultó en una protección de los eritrocitos en ambos sexos. El daño genético disminuyó significativamente por el tratamiento con piruvato de etilo solo o combinado con amifostina, y en hembras se observó una mayor supervivencia solo con el tratamiento combinado. El piruvato de etilo mostró una acción radioprotectora significativa, que podría mejorarse aumentando la dosis o el tiempo de tratamiento, ya que tiene muy baja toxicidad.