The role of conjugation reactions in detoxication

Abstract

The role of conjugating enzymes is best understood by looking at the interaction between phase I (mostly cytochromes P-450) and phase II (conjugation) enzymes of drug metabolism. A balance between phase I and II enzymes of detoxication largely determines the disposition to drug toxicity. Reactive electrophilic metabolites, generated by phase I enzymes, are often controlled by GSH-transferases, whereas nucleophilic metabolites such as phenols are controlled by UDP-glucuronosyltransferases (GT) and sulfotransferases. It is more and more recognized that the control of the more stable and more abundant nucleophiles is as important as the control of electrophiles, since the former can be readily converted to electrophiles. For example, phenols and quinols can undergo quinone/quinol redox-cycles with the generation of reactive oxygen species. In the case of benzo(a)pyrene-3,6-quinol toxicity can be prevented by glucuronidation. Conjugating enzymes consist of families of isoenzymes with distinct but overlapping substrate specificity. Rather than dealing with individual isoenzymes, adaptive programs are emphasized by which gene expression of a battery of phase I and II enzymes is turned on by certain types of inducing agents. Mechanistically best known is the program turned on by 3-methylcholanthrene-type inducers which includes enhanced synthesis of certain isoenzymes of cytochrome P-450, GT and probably GSH-transferase. The program may adapt the organism to efficiently detoxify and eliminate aromatic compounds such as benzo(a)pyrene. Evidence is presented that this program exists in both rodents and humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

“…Glucuronidation facilitates the elimination of inactive hydrophilic glucuronides from the body via urine or bile [1,2]. In general, glucuronidation is thought to serve as an inactivating or protective function by terminating or attenuating the activity of many endogenous, dietary and clinically administered drugs as well as environmental chemicals that have been shown to result in toxicity or carcinogenesis [2].…”

“…Glucuronidation facilitates the elimination of inactive hydrophilic glucuronides from the body via urine or bile [1,2]. In general, glucuronidation is thought to serve as an inactivating or protective function by terminating or attenuating the activity of many endogenous, dietary and clinically administered drugs as well as environmental chemicals that have been shown to result in toxicity or carcinogenesis [2]. However, glucuronidation also can result in the generation of bioactive or even toxic compounds, including those of estrogens, morphine, retinoids, bile acids, and heterocyclic aromatic amines [3][4][5][6][7].…”

Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer

“…Estrogen metabolism by UGTs is the major drug-metabolic pathway that results in the complete inactivation of estrogens and their hydroxylated metabolites [9–12]. Alterations in UGTs, resulting in decreased UGT expression and glucuronidation activity towards estrogens and their metabolites, has been suggested to play a potential role in breast cancer risk [14–16].…”

“…One of the major pathways involved in estrogen inactivation and removal from circulation is through the process of glucuronidation, catalyzed by UDP-Glucuronosyltransferases (UGTs) [9]. UGTs have the catalytic capacity to inactivate estrogens and their oxidative metabolites to inactive metabolites [10–12].…”

Novel identification of UDP-glucuronosyltransferase 1A10 as an estrogen-regulated target gene

“…UGTs are membrane-bound glycoproteins localized in the endoplasmic reticulum and nuclear envelope [9]. UGTs are defined by their ability to catalyze the transfer of glucuronic acid from the co-substrate UDP-glucuronic acid (UDP-GA) to a wide range of hydrophobic endogenous and exogenous substrates generating more polar, generally inactive molecules that can be readily excreted from the body in the urine or bile [10,11]. However, UGTs can also generate bioactive, perhaps toxic compounds, including those of steroid hormones, morphine, retinoids, and bile acids [12][13][14][15][16].…”