Main Features of Ethanol Metabolism
Ethanol is absorbed from the gastrointestinal tract by rapid diffusion mostly in the duodenum and upper jejunum, although some are metabolized in the stomach (Rome et al., 1991, Oneta et al., 1998). ‘
There are three metabolic pathways for the oxidation of ethanol to acetaldehyde; the alcohol dehydrogenase (ADH) pathway, the microsomal ethanol oxidizing system (MEOS) and the catalase pathway. The further oxidation of acetaldehyde to acetate is catalyzed by aldehyde dehydrogenase (ALDH).
Alcohol Dehydrogenase (ADH)
The main enzyme that catalyzes the oxidation of ethanol to acetaldehyde is ADH (Bosron and Li, 1986), a cytosolic enzyme that is expressed in tissues as several isoenzymes with different kinetic properties and substrate preferences. The incidence of these isoforms varies between racial groups. (Jornvall and Hoog, 1995, Eriksson et al., 2001). Some studies of its tissue distribution have indicated that ADH is enriched in zone 3 hepatocytes (Buehler
Some studies of its tissue distribution have indicated that ADH is enriched in zone 3 hepatocytes (Buehler et al., 1982, Yamauchi et al., 1988), although it has been reported elsewhere to be distributed homogenously throughout the lobule. (Watabiki et al., 1999).
Consequently, since the liver is the primary site for ethanol metabolism, it is also a major target for ethanol toxicity. (French 1989, Nanji
Consequently, since the liver is the primary site for ethanol metabolism, it is also a major target for ethanol toxicity. (French 1989, Nanji et al., 2002). Some positive associations between ADH genotype and alcohol induced liver injury, or even alcoholism, have been reported. (Sherman et al., 1993, Nakamura et al., 1996).
Cytochrome P450 in Ethanol Metabolism (MeOS)
A cytochrome P450-mediated pathway also contributes to ethanol metabolism (Lieber 1988, Asai et al., 1996, Caro and Cederbaum, 2004). An important characteristic of this pathway is that it is induced by chronic ethanol consumption, so that its capacity to metabolize ethanol is increased (Lieber and DeCarli, 1968), as commonly observed after long-term alcohol drinking.
It is generally agreed that this effect is due to an increase in hepatic ethanol-inducible cytochrome P4502E, (CYP2E1), which is the major catalytic component of MEOS (Ingelman-Sundbery et al., 1988, Lieber 1999). CYP2E1 catalyzes the oxidation of ethanol to acetaldehyde, a reaction in which the oxidation of ethanol is coupled to the reduction of oxygen using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a hydrogen donor.
Upon chronic ethanol consumption, both the content and catalytic activity of CYP2E1 will increase, and consequently acetaldehyde production by MEOS will be enhanced. Immunoblot analysis of human liver microsomes has shown that their CYP2E1 content is several times higher in alcoholics who have been drinking recently than in non-drinkers.
In both rats and man, CYP2E1 is normally localized in the perivenular region or zone 3, of the liver lobule, and its induction by prolonged alcohol consumption occurs primarily within this acinar region. (Tsutsumi
In both rats and man, CYP2E1 is normally localized in the perivenular region or zone 3, of the liver lobule, and its induction by prolonged alcohol consumption occurs primarily within this acinar region. (Tsutsumi et al., 1989, Cohen et al.,1997, Fang et al., 1998). CYP2E1 is also present in hepatic
CYP2E1 is also present in hepatic kupffer cells, suggesting that, under conditions where it is induced, metabolites generated in the kupffer cells may increase toxicity and lipid peroxidation in these cells and induce hepatic injury. (Cederbaum 1989, Koop et al., 1991, Nakamura et al., 1999).
Minor amounts of ethanol may be oxidized by peroxisomal catalase. As its activity depends on hydrogen peroxide production, which is very low in the liver under normal circumstances, the role of catalase in ethanol oxidation is probably very small, although it could be implicated in other tissues such as the brain (Cohen et al., 1980, Aragon et al., 1991, Rintala et al., 2002) nevertheless, it has been suggested that some of the ethanol metabolism in the liver may be catalase dependent (Thurman and Handler 1989).
First – Pass Metabolism of Ethanol
The gastric wall is a major site for the metabolic pathway defined as first-pass metabolism of ethanol (Gentry et al., 1994). The stomach also contains ADH, and both it and the liver have the same class I and III ADH isoenzymes. In addition, the class IV ADH isoform total ADH activity in the stomach, which may also be regarded as a barrier against the penetration of excess alcohol into the body. A significant correlation exists between overall gastric ADH activity and first-pass metabolism (Frezza
A significant correlation exists between overall gastric ADH activity and first-pass metabolism (Frezza et al., 1990). Women have lower total gastric ADH activity and higher blood ethanol levels after ethanol consumption and it has been speculated that this may explain their higher susceptibility to ethanol-induced toxicity (Frezza et al., 1990, Schenker 1997).
Intestinal Metabolism And Ethanol Metabolism
It has been shown recently that the gastro intestinal microflora can also metabolize ethanol, as the microbes of the alimentary tract participate in the metabolism of exogenous ethanol (Solaspuro, 1996). High concentrations of acetaldehyde may be generated through this pathway in humans, since the intestinal capacity for acetaldehyde removal is low, causing acetaldehyde to accumulate in the gastrointestinal tract.
Formation of Acetaldehyde Protein Adducts
Acetaldehyde, the first metabolite of ethanol and the aldehydric products of lipid peroxidation that are generated during ethanol induced oxidative stress can bind to proteins and cellular constituents to form stable adducts (Israel et al., 1986, Tuma and Sorell 1987, Trudell et al., 1991). Acetaldehyde can bind to reactive amino acid residues in several target proteins (Stavens et al., 1981, Israel et al., 1986, Behrens et al.,1990, Wehr et al., 1993, Tuma and Sorrell 1995, Zhu et al., 1996). In vitro studies have shown the formation of acetaldehyde adducts with haemoglobin and plasma proteins, including albumin (Donohue
In vitro studies have shown the formation of acetaldehyde adducts with haemoglobin and plasma proteins, including albumin (Donohue et al., 1983, Israel et al., 1986). And there are several other proteins that can also efficiently bind acetaldehyde, including erythrocyte membrane proteins (Gaines et al., 1997), tubulin (Smith et al., 1989), lipoproteins (Wehr et al., 1993, Lin et al., 1995, Paradis et al., 1996), collagens (Jukkola and Niemela 1989, Behrens et al., 1990), ethanol inducible CYP2E1 (Behrens et al., 1988) and Ketosteroid reductase (Lin et al., 1988).
The acetaldehyde adducts can be either unstable or stable in nature (Tuma and Sorrell 1995). Unstable Schiff base adducts are formed by the binding of acetaldehyde to lysine residues, which are then further stabilized by reduction. Free E-amino lysine groups are important targets for adduct formation (Tuma
Free E-amino lysine groups are important targets for adduct formation (Tuma et al., 1987). Lysine residue in a critical location, as reported for tubulin (Smith et al., 1989) and for lysine – dependent enzymes (Mauch et al., 1986). Spontaneous stabilization of linkages has being observed to occur between acetaldehyde and the - amino groups of haemoglobin in reactions yielding stable imidazolidinone derivatives (George and Hoberman 1986, Fowles et al., 1996).
Acetaldehyde Adducts With Hemoglobin
cetaldehyde haemoglobin condensates may be generated both in vitro and in vivo following ethanol ingestion (Sorrell and Tuma 1987, Nicholls et al., 1992). Cyclic imidazolidinone derivatives are formed between acetaldehyde and the free - amino groups of the amino terminal valine of haemoglobin (george and Hoberman 1986). Lysine residues have been implicated as major targets for acetaldehyde adducts.
The peptides Val-His-Leu-thr-Pro and Val-His-Leu-Thr-Pro-Val-Glu-Lys in the amino terminus of the β – globin chain of haemoglobin have at least one potential site for adduct formation (Fowles et al., 1996, Braun et al., 1997). In the octapeptide, the N – terminal amino group of valine and the E – amino group of lysine can be modified by acetaldehyde.
Haemoglobin adducts appear to be stable at 37c for up to 14 days, which means that these stable Schiff base products can serve as markers of ethanol consumption and explain some clinical consequences of ethanol abuse (Stevens et al ., 1981, Niemela and Israel., 1992, Braun et al ., 1997).