Ethanol enzyme induction with

P450 enzymes may also be induced by substrate stabilization, eg, decreased degradation, as is the case with troleandomycin- or clotrimazole-mediated induction of CYP3A enzymes, the ethanol-mediated induction of CYP2E1, and the isosafrole-mediated induction of CYP1A2. 

Hepatic depletion of vitamin A stores is caused by chronic ethanol consumption (Bonjour, 1981). Night blindness suffered by alcoholics has been attributed to a low intake of vitamin A (McClain et aL, 1979). However, Sato and Lieber (1982) have demonstrated that ethanol depletes hepatic vitamin A stores in baboons and rats even when it is administered in combination with a nutritionally adequate diet. In addition, animals consuming ethanol in marginal diets were depleted more rapidly of vitamin A. No effect of ethanol intake on retinol binding protein or on serum vitamin A levels could be detected in these studies. Leo and Lieber (1982) found that hepatic vitamin A was depleted to one-fifth of normal levels in alcoholics with only moderate liver disease. Sato and Lieber (1982) observed that retinoic acid was more rapidly metabolized by the MFO system after chronic ethanol intake, and they postulated that vitamin A depletion was the result of MFO enzyme induction. 

Induction by increased enzyme synthesis has been described for induction of CYP2B1/2 by octamethylcyclotetrasiloxane (Sarangapani et al. 2002) and CYP1A1 and CYP1A2 by TCDD via interaction with the Ah-receptor (Andersen 1995 Andersen et al. 1997). Induction by decreased enzyme degradation has been described by Chien et al. (1997) for induction of CYP2E1 by ethanol, acetone, and isoniazid via enzyme stabilization. Exposure to such enzyme inducers and stabilizators would result in increasing the clearance of all other coexposed chemicals that are metabolized by the stabilized enzyme. 

Metabolism also plays a critical role in the pharmacology of cocaine. The rapid hydrolysis of cocaine via two different pathways leads to its rapid inactivation/detoxification. This rapid metabolism has been a major determinant in the methods and modes of cocaine abuse. Identification and characterization of these hydrolytic enzymes would be useful in that selective induction of these enzymes offers a potential treatment strategy for dealing with cocaine overdose. It is conceivable that long-term elevation of the enzyme or enzymatic activity could be used in conjunction with maintenance therapy for cocaine addicts. Hydrolases or esterases are also responsible for the transesterfication of cocaine. The pharmacological effect of cocaine is prolonged and enhanced when cocaine is used in conjunction with ethanol. A carboxylesterase catalyzes an ethyl transeterification of cocaine to cocaethylene, which is biologically active. 

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. 

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). 

The maximal capacity of MEOS (cytochrome P450-2E1) is increased in the liver with continued ingestion of ethanol through a mechanism involving induction of gene transcription. Thus, Al Martini has a higher capacity to oxidize ethanol to acetaldehyde than a naive drinker (a person not previously subjected to alcohol). Nevertheless, the persistance of his elevated blood alcohol level shows he has saturated his capacity for ethanol oxidation (V-maxed out). Once his enzymes are operating near Vmax. any additional ethanol he drinks will not appreciably increase the rate of ethanol clearance from his blood. 

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