Induction ethanol causing

In animals, chronic ethanol causes induction of hepatic microsomal enzymes, and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoenzyme is important in the oxidative metabolism of paracetamol). This conclusion is not yet fully documented in man. 

Caffeine causes intracellular calcium levels to increase and thereby increases apoptosis induction. Ethanol promotes higher calcium levels and higher apoptotic rates than caffeine. When caffeine and ethanol are combined, calcium levels and apoptosis are markedly elevated, indicating that the apoptotic effect of ethanol is potentiated when it is mixed with caffeine... 

Chronic use of ethanol causes induction of a cytochrome P450 isozyme that converts acetaminophen to a cytotoxic metabolite. This appears to be the explanation for the increased susceptibility of alcoholics to hepatotoxicity with overdose of acetaminophen. The answer is (D). 

Zinc dust is frequently covered with a thin layer of zinc oxide which deactivates its surface and causes induction periods in reactions with compounds. This disadvantage can be removed by a proper activation of zinc dust immediately prior to use. Such an activation can be achieved by a 3-4-minute contact with very dilute (0.5-2%) hydrochloric acid followed by washing with water, ethanol, acetone and ether [/55]. Similar activation is carried out in situ by a small amount of anhydrous zinc chloride [156 or zinc bromide [157 in alcohol, ether or tetrahydrofuran. Another way of activating zinc dust is by its conversion to a zinc-copper couple by stirring it (180g) with a solution of 1 g of copper sulfate pentahydrate in 35 ml of water [/55]. 

Meanwhile, the data obtained [87, 116] unambiguously indicate that the catalase activity increase is associated with non-classical peroxidase activity intensification. It is obvious that the last circumstance casts some suspicion on the interpretation of reactions (6.17) and (6.18) as the competing ones, because in this case, intensification of one reaction should cause suppression of the other. Moreover, as follows from Kremer s data [118], the catalase reaction rate is five orders of magnitude higher than the peroxidase reaction rate. Therefore, comparison of these reactions from competition positions is very suspect. An article by Chance and coworkers [119] can be mentioned as evidence that a H202 concentration increase in the system in the presence of ethanol intensifies peroxidase activity (hence, intensification of the catalase activity is implied). Because catalase activity increase causes the Chance complex formation at higher rate, the peroxidase reaction (6.18) rate is also increased owing to chemical induction principle. 

Human CYP2E1 is one of the most efficient P450s to catalyze the oxidation of acetaminophen to NAPQI (157-159). Ethanol and isoniazid cause a time-dependent inhibition and induction of acetaminophen oxidation to NAPQI in humans (160,161) that can decrease risk for hepatotoxicity over the interval of concurrent administration and increase risk for hepatotoxicity a few hours after removal of ethanol or isoniazid. The latter induction phase of CYP2E1 may, in part, be responsible for cases of acetaminophen hepatotoxicity associated with the use of ethanol (162-165) or isoniazid (166-168). However, the induction is modest (2- to 3-fold) therefore, other susceptibility factors, genetic and others such as decreased glutathione stores and nutritional status, are likely to play an important role in some individuals (169-174). 

The following are examples of the effect of ethanol on nutritional components and drugs that are caused by metabolic induction. 

Limited data from animal studies (Woolverton and Balster 1981) indicate that alcohol drinkers may be more susceptible to the acute neurobehavioral effects of 1,1,1-trichloroethane. Moderate to heavy alcohol drinkers may be more susceptible to the hepatotoxicity of some chlorinated alkanes, such as carbon tetrachloride, chloroform, and 1,1,2-trichloroethane, due to ethanol induction of hepatic cytochrome P-450 isozymes involved in the activation of these compounds to intermediate hepatotoxic metabolites. Available animal studies (Cornish and Adefuin 1966 Klaassen and Plaa 1966, 1967), however, have not demonstrated that ethanol ingestion will potentiate the hepatotoxicity of 1,1,1-trichloroethane. Furthermore, evidence indicates that ethanol does not cause... 

A coal tar solution (crude coal tar diluted to 20% with ethanol and polysorbate 80) was applied to clinically unaffected skin of three patients with severe atopic dermatitis and six patients with generalized psoriasis (Bickers and Kappas 1978). Another skin area at least 10 cm away was not treated or was treated with 100 mL of the vehicle alone. Twenty-four hours later, a 6-mm punch biopsy was obtained from coal tar treated and control areas and the effect on AHH activity was determined. Application of coal tar to the skin caused induction of cutaneous AHH activity that varied from 2.4- to 5. 4-fold over the enzyme activity in untreated skin areas, suggesting absorption after topical application. 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

Drug Interactions Barbiturates combine with other CNS depressants to cause severe depression ethanol is the most frequent offender, and interactions with first-generation antihistamines also are common. Isoniazid, methylphenidate, and monoamine oxidase inhibitors also increase the CNS-depressant effects. Other prominent drag interactions occin as a result of the induction of hepatic drug-metabolizing enzymes by barbiturates see above). 

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