Glucuronidation enzymes, genes and psychiatry

Abstract

The phase I cytochrome P450 (CYP) isoenzymes have received substantial attention in the pharmacogenetic literature. Researchers are beginning to examine the role of the phase II UDP-glucuronosyltransferase (UGT) enzymes, which produce products that are more water-soluble, less toxic and more readily excreted than the parent compounds. Several reasons may have contributed to neglect of UGTs (compared to CYPs) including: (1) the overlapping activity of UGTs and lack of selective probes; (2) the complexity of the glucuronidation cycle; and (3) the difficulty in developing analytic methods to measure glucuronides. Current CYP knowledge is used as a model to predict advances in UGT knowledge. At least 24 different UGT human genes have been identified and are classified in two families (UGT1 and UGT2) based on sequence homology. The UGT1A subfamily (genes located on chromosome 2) glucuronidates bilirubin, thyroid hormones, and some medications. UGT1A4 metabolizes tricyclic antidepressants and some antipsychotics. The UGT2B subfamily (genes located on chromosome 6) glucuronidates sexual steroids and bile acids. Oxazepam and lorazepam are mainly metabolized by glucuronidation. Anti-epileptics with mood-stabilizing properties are frequently metabolized by UGTs. Opioid and nicotine addiction may also be influenced by glucuronidation. Glucuronidation of serotonin may be important during fetal development. UGTs appear to be in small concentrations in brain tissue (and higher concentrations at brain capillaries). However, UGTs may be localized in certain brain areas to provide a neuroprotective function. This review illustrates the importance of glucuronidation and the implications for psychiatry.

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

“…3,34,36) Many therapeutic drugs, some of which target brain tissues, such as analgesics, anticonvulsants, or antipsychotics are UGT substrates. 37) Moreover, it has been reported that the glucuronide of the monoamine neurotransmitters, dopamine and serotonin, had been observed in human and rat brains. [38][39][40] Maintaining the proper concentration of a substance in a target site (specific brain region or neurons) is important to perform an effective and safe drug therapy or to maintain homeostasis.…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…-After oral administration, the drug is rapidly absorbed. Only 27-50 % of the dose reaches the systemic circulation unchanged because of extensive first-pass metabolism (25)(26)(27)(28). It is 95 % bound to plasma proteins, primarily alpha-1-acid glycoprotein.…”

Pharmacogenetics of Nicotine Metabolism in Twins: Methods and Procedures

“…Variation among racial groups also exists in other nicotine metabolic pathways such as nicotine and cotinine glucuronidation (Benowitz et al, 1999). This suggests that additional differences in the rates of nicotine metabolism among racial groups may be due to variation in the frequencies of allelic variants in genes responsible for nicotine-N-1-oxidation (i.e., flavin containing monooxygenase 3 gene; Cashman et al, 1995) and glucuronidation (i.e., UDP-glucuronyltransferase genes; de Leon, 2003;Nakajima et al, 2002). For these reasons, we plan to pursue a twin study of nicotine metabolism in other racial populations in the near future (e.g., Yang et al, 2002).…”