title: Strategic Drug Design to Avoid the Metabolic Activation of Hepatotoxic Drugs.
abstract: Adverse reactions are one of the most important issues in drug development, as well as in the therapeutic usage of drugs during the post-approval stage. Specifically, idiosyncratic adverse drug reactions (IDR) occur in only a small group of patients who are treated with certain drugs, and are unpredictable. It is widely accepted that drug-induced IDR is often associated with CYP-mediated bioactivation. Benzbromarone (BBR) is effective in the treatment of hyperuricemia, and has been used as an effective drug in Japan for a long time. However, BBR has been associated with hepatotoxicity, including fatal liver injury. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (CAT) as novel metabolites of BBR in human and rat liver microsomal systems, by comparison with chemically synthesized authentic compounds via ipso-substitution, which we previously discovered to be a unique metabolic reaction of substituted phenols by CYP. Furthermore, CAT, DBH and the oxidized form of DBH (DBBQ) were highly cytotoxic in human hepatocellular carcinoma cells, compared with BBR. We consider that the formation of these metabolites from BBR is linked to the mechanism involved in BBR-induced hepatotoxicity because catechols, hydroquinones, and their oxidized forms are known to be toxic.
authors.affiliation: Faculty of Pharmacy, Keio University.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
mesh_terms: D001553:Benzbromarone / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D002396:Catechols / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D015195:Drug Design; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity; D033461:Hyperuricemia / Q000188:drug therapy; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D002396:Catechols; D006873:Hydroquinones; D001553:Benzbromarone; D003577:Cytochrome P-450 Enzyme System; C031927:hydroquinone