TOX 4000 Lecture Notes - Lecture 4: Glutathione Reductase, Uridine Diphosphate, Glutathione
13 Oct 2018
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Lecture 4: phase 2 reactions sept. 17. But: xenobiotic may be eliminated after phase 1, xenobiotic may be conjugated by phase 2 directly. Xenobiotic substrates of gsh: hydrophobic, contain electrophilic atom, react nonenzymatically with gsh. Detoxification: electrophiles are potentially toxic by binding to critical nucleophiles, all biotransforming enzymes have the potential to create reactive intermediates. Glucuronidation: glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid (udpga) to a substrate by any of several types of udp- glucuronosyltransferase (ugt) Nutritional and drug-drug interactions: decreasing the cofactor udpga can predispose to acetaminophen toxicity. Induction of ugts nicotine, cabbage, and brussel sprouts can enhance glucuronidation of acetaminophen (ugt isoenzyme ugt1a6 is inducible) Inhibition of ugts valproic acid inhibits ugts, thereby increasing plasma auc (actual body exposure to the drug) for the ugt/glucuronidation targets lorazepam and carbamazepine. Cbz metabolism hindered by cyp3a4 inhibitors: phase 2: glucuronidation.
