All organisms are continuously exposed to potentially toxic or adverse chemicals from the environment. Whenever such substances are not naturally produced by the organism itself, or are not expected to be within the organism, they are called xenobiotics. Xenobiotics are mostly of no nutritional value and have no metabolic function. Before they may effectively be excreted, most xenobiotics undergo biotransformation. Generally, there are two types of biochemical biotransformation reactions known as phase I and phase II reactions (Figure 16), according to a concept introduced in 1947 by Roger Williams.87 Even though the aim of biotransforming xenobiotics is detoxification and elimination, it can also lead to an increase in toxicity. An example is aflatoxin B1 that is activated by phase I …show more content…
It is a more often observed biotransformation pathway for small endogenous compounds, but also plays a role in the metabolism of macromolecules like nucleic acids. Compounds can undergo N-, O-, S- and arsenic methylation catalyzed by enzymes called methyltransferases, employing S-adenosylmethionine as the methyl donor.95,98 Amino acid conjugation reactions are a route of metabolism of xenobiotic carboxylic acids. The enzymes of conjugation reside in mitochondria. Mechanistically, it differs from the other conjugation reactions. It involves initial activation of the carboxylic acid moiety with ATP, generating an acyl adenylate and pyrophosphate. Bound acyl adenylate reacts with coenzyme A (CoASH) to yield a high energy xenobiotic-CoA thioester intermediate that will link the activated acyl group to the amino group of the acceptor amino acid with regeneration of CoASH.101 Glutathione conjugation involves conjugation of the tripeptide glutathione with a xenobiotic that is enzymatically catalyzed by glutathione transferases. The detoxification pathway of xenobiotics via glutathione is discussed in