Bioactivation - Toxicology PDF

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Write an essay on either (a) metabolic activation (bioactivation) of chemicals. Include in your answer specific examples.  Biotransformation is essential to convert lipophilic chemicals to water-soluble ones so they (the metabolites) can be more easily excreted. These reactions are categorised into phase I and phase II metabolism. Phase I reactions involve the introduction of functional groups and phase II reactions involve the conjugation of such functional groups with endogenous, polar products. Biotransformation plays an essential role in the toxicity of many chemicals due to the metabolic formation of toxic metabolites.  Bioactivation occurs during drug metabolism and often initiates drug toxicity...when the metabolite is more active (and more toxic) than the parent compound. The CYP450 and peroxidase enzyme systems are generally considered the most important groups of enzymes involved in bioactivation, producing either electrophilic or radical metabolites.

 Bioactivation occurs more commonly in metabolites of phase I metabolism. If the metabolite from phase I is stable, it can either undergo further metabolism or be excreted from the body. Reactive metabolites produce toxic effects in the body and must undergo further metabolism before they can be excreted.

 Phase I metabolic reactions comprise of oxidation, hydration, hydrolysis and reduction. In some cases, a drug can be metabolised in one species to produce a stable metabolite but can form an active, toxic metabolite in a different species due to differences in the phase I reaction pathway. For example, malathion, an insecticide, has selective toxicity for insects and so does not cause comparable adverse effects in mammals. This is due to the phase I reaction pathway. In mammals, malathion undergoes hydrolysis and forms a stable metabolite that is no more active than the parent compound. However, in insects, oxidation occurs bringing about the active form of malathion, malaoxon. This example shows the adverse effects of bioactivation of melatonin in insects and also illustrates that just because a compound is activated in one species does not mean it's activated in a different species and therefore bioactivation is dependent on the metabolic pathway.

 The term prodrug is used to describe any drug or compound that, after administration and distribution, are metabolised to form pharmaceutically active drug metabolites that produce a desired effect. These drugs are formulated in an inactive form that is designed to break down inside the body to form the active drug. For example, codeine, an opiate used to treat pain (analgesic), is inactive until it is metabolised in the liver to morphine and other metabolites. Codeine itself has a low affinity for opioid receptors and is less potent than its metabolites. The active metabolites of codeine, for example, morphine, are responsible for the majority of the analgesic effects of codeine. Codeine is converted into morphine by cytochrome P450 enzyme CYP2D6. Morphine and the other metabolites are stronger (more active) than codeine so in this example bioactivation leads to the formation of a metabolites that are responsible most of the therapeutic action of the parent drug.

 Sometimes bioactivated metabolites may produce toxic effects and patients must be monitored carefully to ensure they do not build up in the body.  Halothane, a potent general anaesthetic that is inhaled, is associated with hepatotoxicity, resulting in liver problems. This is caused by bioactivation of halothane after it begins to metabolise. Effects can be mild or severe….2 types of hepatotoxicity caused by halothane...reason why use of halothane decreased in the 80s..  The first results in mild transient (short-lived) liver dysfunction. This effects 20% patients that receive halothane. It is referred to as direct toxicity. The onset is prompt and the effects are short-term and dose-related. May result from reductive (anatomical) bioactivation of halothane following phase I metabolism rather than the normal oxidative pathway.  The second type of hepatotoxicity caused by metabolism of halothane to active metabolites is very severe and results in liver damage in...