Vitamin B6 metabolism in chronic alcohol abuse The effect of ethanol oxidation on hepatic pyridoxal 5'-phosphate metabolism.

Abstract

A B S T R A C T Individuals with chronic alcohol abuse frequently exhibit lowered plasma levels of pyridoxal 5'-phosphate, the coenzyme form of vitamin Be. Because the liver is the primary source of this coenzyme in plasma and also the principal organ that oxidizes ethanol, the effect of ethanol on hepatic pyridoxal phosphate metabolism was studied in the rat. The chronic feeding of ethanol (36% of the total dietary calories) for 6 wk significantly decreased the hepatic pyridoxal phosphate content both in animals given a sufficient amount of vitamin Be in their diet and in those rendered vitamin Be deficient. In isolated perfused livers, the addition of 18 mM ethanol lowered the pyridoxal phosphate content of livers from vitamin B.-sufficient animals and decreased the net synthesis of pyridoxal phosphate from pyridoxine by the livers of vitamin Be-deficient animals. Ethanol also diminished the rate of release of pyridoxal phosphate into the perfusate by the livers of vitamin Be-deficient rats. These effects of ethanol, in vitro, were abolished by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Thus the derangement of pyridoxal phosphate metabolism produced by ethanol is dependent upon its oxidation. These data support previous findings which indicate that acetaldehyde is the responsible agent which acts by accelerating the degradation of intracellular pyridoxal phosphate.This work was presented at the Annual Meeting of the Central Society for Clinical Research, Chicago, Ill. (1974 Since the liver is the principal organ responsible for the oxidation of ethanol, the nature of the derangement in PLP metabolism can be most directly elucidated by studies with hepatic tissue. The liver also plays a central role in the metabolism of vitamin Be: a major portion of the pyridoxine absorbed by the intestine is accumulated by liver (3) and PLP in plasma is derived principally from the liver (4). In this communication, we report both the effect of chronic ethanol administration upon the hepatic PLP content of rats and the acute effect of ethanol oxidation upon PLP metabolism in isolated perfused rat livers.Isolated perfused livers have not been previously employed to study PLP metabolism. In the course of 'Abbreviation used in this paper: PLP, pyridoxal 5'-phos- METHODSExperimental animals. All animals were male SpragueDawley rats (Laboratory Supply Co., Indianapolis, Ind.), housed in wire-bottomed cages and in a controlled temperature environment with fixed day-night cycles. To study the chronic effect of ethanol on hepatic PLP content in vivo, rats were pair-fed the liquid diets as described by Lieber and DeCarli (5). The alcohol diet contained 18% of the calories as protein, 35% as fat, 11% as carbohydrate, and 36% as ethanol. The control diet was identical except that ethanol was isocalorically replaced with dextrin-maltose. Both diets contained 0.725 ,ug pyridoxine-HCl/ml. Rats weighing 150-170 g were pair-fed these diets for 52+3 days and were considered to be vitamin B. sufficient. Another group of rats was ...

The Role of Acetaldehyde in Mediating the Deleterious Effect of Ethanol on Pyridoxal 5′-Phosphate Metabolism

“…We have previously reported that ethanol oxidation decreases the hepatic content of PLP in isolated perfused rat livers (5). In the present study with isolated hepatocytes, ethanol oxidation has no demonstrable effect on cellular PLP content unless acetaldehyde oxidation was inhibited concomitantly (Fig.…”

“…Whereas pyridoxic acid is biologically inactive, PLP and pyridoxal are the transport forms in plasma. Ethanol oxidation lowers hepatic PLP and impairs the release of this coenzyme (5). As shown here, acetaldehyde also decreases hepatic PLP; however, its effect on the release of PLP and pyridoxal has not been defined.…”

“…In experimental animals, PLP in plasma is derived almost entirely from liver, and its concentration is determined both by hepatic synthesis and by degradation (4). We have reported that the oxidation of alcohol by isolated perfused rat livers curtails both the release of PLP into the perfusion medium and lowers hepatic PLP content (5). These deleterious effects of alcohol on PLP metabolism are abolished by 4-methylpyrazole, a specific inhibitor of alcohol dehydrogenase, suggesting that acetaldehyde may be the causative agent (5).…”

“…We have reported that the oxidation of alcohol by isolated perfused rat livers curtails both the release of PLP into the perfusion medium and lowers hepatic PLP content (5). These deleterious effects of alcohol on PLP metabolism are abolished by 4-methylpyrazole, a specific inhibitor of alcohol dehydrogenase, suggesting that acetaldehyde may be the causative agent (5). Indeed, incubation of human erythrocytes with 0.05-1 mM acetaldehyde impairs the net conversion of pyridoxine to PLP (3).…”

Chromosomal Aberrations in the Lymphocytes of Alcoholics and Former Alcoholics

“…increase of esophageal [29], laryngeal [26] and oral cancer [28], high mortality in cardiovascular disease [12], nutrient deficiency [11,23,27], and brain dysfunction [13]. Among women of reproductive age, epidemiological studies have shown that ethanol consumption during pregnancy causes in creased spontaneous abortion and intrauterine growth retardation [20,25], Several reports have described an association between maternal alcoholism and a recogniz able pattern of fetal anomalies termed fetal alcohol syn drome [1,4], Thus, alcohol is suspected of possessing cancerogenic, mutagenic and teratogenic potentials.…”