Detoxification of xenochemicals and toxins is vital for optimal health. There are a myriad of ways that this is achieved, but the primary mechanism involves biotransformation reactions performed by drug metabolising enzymes (DME). The detoxification process is split into an oxidative phase and conjugative phase, and these have an overlapping function that ultimately increases lipophilicity and aids excretion in the urine or faeces. Phase I detoxification involves the cytochrome P450 (CYP) group of enzymes, a group of membrane bound proteins with mixed function monooxygenase activity. Isoforms of CYP can be found in many tissues, but primarily they are located on the smooth endoplasmic reticulum of hepatocytes and the enterocytes of the small intestine. The phase II detoxification system includes a wide variety of enzymes also found mainly in the endoplasmic reticulum of the liver and intestine. Phase II enzymes conjugate various compounds to phase I products.
Phase I detoxification is an oxidative process that is essential in order to increase the lipophilicity of xenobiotic compounds. Generally the phase I metabolic process deactivates the xenobiotic, but in some cases reactivity increases, and this is often a necessary activation step for phase II metabolism. There are a large number of gene families of CYP enzymes in humans, but generally CYP1, CYP2 and CYP3 families are involved in the vast majority of biotransformations in humans. The CYP3A4 protein is the main isoform present in the liver, and the CYP3A family represents 30% and 70% of CYP activity in the liver and small intestine, respectively. The phase I detoxification ability of an individual can be measured by using caffeine detoxification rates as a biomarker of CYP. Humans can display up to a five fold variation in caffeine detoxification indicating wide ranging polymorphism in CYP genes.
Phase II metabolism involves the conjugation of smaller compounds to xenobiotics using transferase enzymes. Often a compound will need activation by phase I enzymes, before phase II metabolism can proceed, but in some cases activation is not required. Phase II metabolism results in a less toxic more highly lipophilic substance that can be excreted in the urine or faeces. The most important phase II enzymes are UDP-glucuronosyl transferase (UGT), glutathione S-transferase (GST), acetyltransferase, sulfotransferase, aminotransferase and methyltransferase that conjugate glucuronide, glutathione, acetyl, sulfate, amino acid and methyl moieties to xenobiotics, respectively. Generally these enzymes require a number of nutrient co-factors to function optimally, and deficiency of these factors can impair detoxification (e.g. selenium deficiency impairs glutathione conjugation). In addition, certain nutrients can induce phase II detoxification. For example isothiocyanates from the Brassica family of plants and limonene from citrus peel can induce glutathione and glucuronide conjugation, respectively.
In addition to DME, there are other non-enzymatic proteins that are involved in the detoxification process. Phase III detoxification involves the use of specific membrane bound transporters to efflux the products of phase I and phase II metabolism from the cell. The ATP-binding cassette (ABC) genes encode the largest known family of transmembrane proteins, and include p-glycoprotein and the multidrug resistance proteins. These proteins utilise ATP hydrolysis to drive the transport of various molecules across all cell membranes. Active transport is required due to the inability of the now lipophilic compound to traverse the cell membrane. The dual location of these transporters on both apical and basolateral membranes of enterocytes of the small intestine suggests that phase III metabolism plays an important barrier function in selective absorption. Efflux of compounds to the gut lumen, as occurs with flavonoids and other xenobiotics, may severely limit their bioavailability and control access to the circulation.
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