Toxicity metabolite induction enhancing

The fact that the same enzyme system can be involved both in lethal synthesis and detoxication can again lead to interactions between different dietary anutrients or drugs. Thus a number of antioxidants (butylated hydroxytoluene, butylated hydroxyanisole, ethoxy-quin ) induce mixed-function monooxygenase, a process which may be considered an adaptive response. As a consequence of this induction, the toxicity of co-administered compounds may be enhanced or reduced, depending on whether the increased activity of the enzymes leads to increased production of toxic or inactive metabolites. In addition, the activity of these pathways is affected by nutritional status, which can further modify the toxic response. The problems of defining a unique no-untoward-effect level are obvious. 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

Caution should be used in patients susceptible to hepatic enzyme induction (e.g. chronic alcohohcs and patients taking enzyme-inducing drugs). Enzyme induction may theoretically enhance the production of toxic metabolites, but currently there is no clear evidence that these interactions... 

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. 

---