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Enzymatic activation of chemicals to toxic metabolites
Abstract:
A variety of enzymes function in the oxygenation, oxidation-reduction, conjugation, and hydrolysis of drugs and other foreign chemicals. Often these enzymes detoxicate chemicals to prevent detrimental effects. In this review we will, however, concentrate on cases in which metabolism activates chemicals to reactive species which cause cellular damage. Particular attention will be given to mixed-function oxidases, which carry out a variety of oxygenations, as well as other reactions. (We will focus on cellular toxicity as opposed to initiation of tumorigenesis in this review.) In many cases, considerable circumstantial evidence exists linking these enzymes to enhanced toxicity of chemicals, although causal relationships have seldom been demonstrated. Further, in very few cases is the explicit cause of toxicity known. Modification of critical protein residues is suspected, although oxidative stress may also be involved in some cases. We discuss general aspects of mechanisms of toxic action, briefly list all cases in which metabolism is suspected to play a role in enhancing toxicity, and review a few examples in detail where substantial chemical and enzymatic information is available. The latter instances would involve knowledge of the enzymes involved, chemical evidence on the structures of the reactive metabolites, identification of adducts, and some inference into the biological processes which are effected to elicit toxicity. We consider, in this regard, vinyl halides (which have been a focus in our own laboratory), acetaminophen, pyrrolizidine alkaloids, and fluoroxene.
Insights
Drug metabolism enzymes can activate chemicals into toxic reactive species, causing cellular damage. This review focuses on how these metabolic activation pathways enhance chemical toxicity, rather than detoxification.
Area of Science:
- Toxicology and Pharmacology
- Biochemistry and Molecular Biology
Background:
- Enzymes typically detoxify foreign chemicals, preventing adverse effects.
- However, some metabolic processes activate chemicals into reactive species, leading to cellular damage and toxicity.
Purpose of the Study:
- To review cases where chemical metabolism activates compounds into toxic reactive species.
- To focus on cellular toxicity mechanisms, excluding tumorigenesis.
- To highlight the role of mixed-function oxidases in metabolic activation and toxicity.
Main Methods:
- Review of existing literature on enzyme-mediated chemical toxicity.
- Discussion of general mechanisms of toxic action.
- Detailed examination of specific examples with available chemical and enzymatic data.
Main Results:
- Circumstantial evidence links metabolic enzymes to enhanced chemical toxicity, though causal links are often unproven.
- Mechanisms of toxicity may involve modification of critical protein residues or oxidative stress.
- Specific examples reviewed include vinyl halides, acetaminophen, pyrrolizidine alkaloids, and fluoroxene.
Conclusions:
- Metabolic activation by enzymes is a significant factor in chemical-induced cellular toxicity.
- Understanding reactive metabolites and their adducts is crucial for elucidating toxicity mechanisms.
- Further research is needed to establish causal relationships and explicit causes of toxicity.