Decreased activity of gastric class III (χ) ADH can explain increased bioavailability of alcohol in women

Abstract

Women are more vulnerable than men to alcohol-induced diseases. This could be due to their higher blood levels. No comparable effect was observed after i.v. administration, suggesting an increased bioavailability of the imbibed alcohol. Furthermore, below the age of 50, this effect was associated with a decrease in total gastric ADH activity, rather than with a lesser rate of ethanol elimination, which in fact may be increased in women. To quantify the difference in bioavailability, the amount of alcohol that reaches the systemic blood after i.v. and oral administration of the same dose (0.3 g/kg body wt.) was compared one hour after a standard meal in 20 men and 17 women. This amount (first-pass metabolism; FPM) was estimated by the differences in areas under the i.v. and oral blood alcohol curves and quantified by integration of the Michaelis-Menten equation over the entire curve of blood concentrations. In women, FPM was 10% of the dose, compared to 21% in men (p < 0.01). It correlated with total gastric ADH activity at 500 mM of ethanol, a concentration likely to occur in the stomach. The gastric mucosa expresses the following 3 classes of ADH isozymes in a decreasing order of affinity for ethanol: ~tADH, a Class I isozyme also present in the liver, zADH, a Class IV ADH characteristic of the upper gastro-intestinal tract, and ~ADH, a Class III isozyme found in most tissues. All of them can operate at the high alcohol concentrations prevailing in the stomach after the drinking of alcoholic beverages. To investigate which isozyme was involved in the gender difference, we used endoscopic biopsy tissue obtained from the gastric corpus of 30 men and 19 women, with normal histology and no H. pylori infection. Activity of the ADH isozymes was assesed by using preferred substrates for Class I (acetaldehyde) and Class IV (m-nitrobenzaldehyde) and a specific reaction of Class III, namely glutathione-dependent formaldehyde dehydrogenase. Since we previously observed an increased bioavailability of imbibed alcohol in Japanese subjects (compared to Caucasians) in association with decreased zADH activity, we focused on this Class IV isozyme. Unexpectedly, there was only a trend for a decrease in Class IV activity in women, with no differences in Class I ADH activity, but there was a 58% reduction in Class III ADH, determined by the formaldehyde dehydrogenase activity (p < 0.003). In summary, 1) an increased bioavailability of imbibed alcohol in women compared to men was confirmed and quantified, 2) this was found to be associated with, and probably due to, a reduced gastric Class III (Z) ADH activity of women compared to men. Since )~ADH is present in most tissues, the significance of a possible decrease in its physiological activity with other substrates is now being explored in various tissues, including the liver.