Metabolism of Endobiotics and Xenobiotics by UDP-Glucuronosyltransferase

Publisher Summary All organisms are exposed to a number of chemical compounds that are toxic were it not for metabolic mechanisms available to the organism to moderate their effects. Chemical substances may be xenobiotics, such as drugs, or compounds presented to the organism from environmental or dietary sources. The elimination of many such compounds and their detoxification involves different types of metabolic reactions. One of them is conjugation through glucuronic acid catalyzed by UDP-glucuronosyltransferases (UGTs). In addition to xenobiotics; endobiotics, such as steroids or bilirubin, are glucuronidated. Formation of glucuronides from xeno- and endo- biotics generally results in the formation of products that are more hydrophilic and more readily excreted by the kidney or liver. A number of UGTs have been purified to homogeneity from liver of several species, including humans. Recently identified are a number of UGTs that are important for the metabolism of xenobiotics and endobiotics, such as steroids and estrogen catechols. This chapter discusses the metabolism of important amines, opioids, and endobiotics, such as steroids and their catechol derivatives. There are details on glucuronidation of amines, glucuronidation of opioid compounds, and glucuronidation of catechol estrogens by UGTs. Many isoforms of UGT catalyze the glucuronidation of primary and secondary amines. In humans, many important therapeutic agents, such as the antihistamines, antipsychotics, and tricyclic antidepressants, are tertiary amines. Many of these tertiary amines, in humans, are converted to and excreted as quaternary ammonium-linked glucuronides. Stably expressed human UGT1.4 protein has been discovered to catalyze the N-glucuronidation of a variety of tertiary amines. To date, only human UGT1.4 has been identified to catalyze the formation of quaternary ammonium-linked glucuronides from tertiary amines. UGT2B1 and UGT1.1 have been demonstrated to catalyze the glucuronidation of opioid substances. UGT2B1 has high activity toward many opioid substrates, whereas UGT1.1 catalyzes the glucuronidation the oripavine-type opioid compounds.