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Detoxification Basics

Elizabeth H. Jeffery, PhD

Almost 50 years ago R.T. Williams first classified detoxification enzymes into phase I (degradative) and phase II (additional) enzymatic reactions. At that time, few of the details we know today were available and very few enzymes were identified. The classification was based on the finding that many xenobiotics, upon entering the liver, are first oxidized (phase I reaction), and then a bulky endogenous compound is added at the site of the oxidation (phase II reaction) before the metabolite is effluxed from the liver into the bile. Remarkably, this classification is still useful, with few exceptions. Recently, as our knowledge of the complexity of the efflux system has increased, scientists have expanded this classification to include the term “phase III” to describe the action of efflux proteins. Efflux proteins belong to the family of ATP binding cassette (ABC) transporters.1,2

The phase I enzyme activities include oxidation, reduction, and hydrolysis reactions. Of these, the major players are the cytochrome P450 (CYP) enzymes, which are found across all 5 biological kingdoms. Approximately 50 different human CYP enzymes have been identified. Intriguingly, studying the diversity in CYPs across species allows us to closely map dates of evolution, based on the estimation that about a 1% mutation in the DNA of CYP genes occurs every 4.5 million years.3,4 From this, one can determine differences in the DNA sequences of divergent CYPs. Plant and animal kingdoms diverged around a thousand million years ago, and vertebrates and non-vertebrates diverged about five-hundred million years ago. Rats and mice only became distinct species some seventeen million years ago. Of the many CYP genes within the human genome, the 3 families expressing CYP 1, 2, and 3 constitute the majority of drug metabolizing detoxification enzymes.5 These enzymes have broad substrate specificity, so that multiple substrates compete for metabolism at a single enzyme. Chronic exposure (= 3-4 days) to a compound that is a substrate for metabolism frequently causes upregulation of enzyme synthesis, resulting in a net increase in activity. In contrast, acute exposure may inhibit and/or destroy the enzyme, causing a net decrease in the rates of metabolism of other compounds that are metabolized by the same enzyme. The net result of induction or inhibition may be recognized as a drug-drug or drug-nutrient interaction.6

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