Clinical and toxicological consequences of the inductive potential of ethanol

Abstract

Variability in drug metabolism is an important factor that accounts for individual responsiveness to xenobiotics. Enzyme induction which leads to a more rapid elimination of foreign compounds and to a more extensive formation of potentially active metabolites significantly contributes to large interindividual variability in drug effects. Ethanol is consumed worldwide in tremendous amounts and is an effective inducer of hepatic drug metabolism, especially involving pathways accomplished by the CYP2E1 isoform of the cytochrome P-450 (CYP) superfamily. Therefore, whenever xenobiotics that are substrates of CYP2E1, such as chlorzoxazone, paracetamol (acetaminophen), halothane, enflurane, methoxyflurane, sevoflurane and many organic solvents (e.g. aniline, trichloroethylene), are taken by an individual who is also chronically consuming ethanol, the accelerated metabolism of these agents and their clinical impact (e.g. decrease in drug activity) and toxicological impact (accumulation of active metabolites) have to be considered. Consequently, in the assessment of drug disposition and action the history of ethanol intake should be carefully evaluated.

Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat

“…It is well known that alcohol can enhance the drug metabolism depending on the activity of the CYP2E1 enzymes (Klotz and Ammon 1998). In contrast, very little has been published on the effects of ethanol on morphine glucuronidation.…”

“…Our interest in naltrexone and methadone was also related to the role these two drugs play in the therapy of heroin addiction. The second goal of our study was to investigate the effects on morphine glucuronidation produced by alcohol, which is known to alter the metabolism of various drugs (Klotz and Ammon 1998;Narayan et al 1991) and is frequently coabused by heroin addicts.…”

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs

“…5a,b Relationship between the chlorzoxazone metabolic ratio (CMR) and the serum enzyme activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICDH) (a), and between the CMR and the excretion rates of HCFC-123 metabolites trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) (b) et al 1995). It is likely that this factor also plays an important role in the susceptibility of humans to HCFC-123 because large variations (up to 50-fold) of CYP2E1 activity have been reported in the population (Klotz and Ammon 1998). The presence of a polymorphic insertion mutation has also been associated with greater CYP2E1 metabolic activity only among individuals who either were obese or had recently consumed ethanol (McCarver et al 1998).…”

“…Elevated CYP2E1 activities can result from genetic polymorphisms, diseases, malnutrition, and from exposure to other chemicals (Lieber 1997(Lieber , 1999Klotz and Ammon 1998). Of the known CYP2E1 inducers, ethanol is the most notable because of its potency and widespread occurrence.…”

Acarbose and acetaminophen-a dangerous combination?

“…Many of the patients described were regular drinkers of alcohol, which is considered to be a risk factor (Table 1). Chronic ingestion of alcohol induces CYP2E1 14 and depletes the hepatic glutathione stores, 15 leading to increased production and decreased degradation of NAPQI and eventually to severe liver damage. Interestingly, acute ingestion of alcohol decreases the toxicity of acetaminophen, probably by inducing a shift of nicotinamide adenine dinucleotide phosphate from the cytosol to the mitochondria, 16 thereby decreasing the function of microsomal oxidative metabolism.…”