Strategic drug design to avoid the metabolic activation of hepatotoxic drugs

Research output: Contribution to journalReview article

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)249-255
Number of pages7
JournalYakugaku Zasshi
Volume137
Issue number3
DOIs
Publication statusPublished - 2017

Fingerprint

Benzbromarone
Drug Design
Pharmaceutical Preparations
Drug-Related Side Effects and Adverse Reactions
Catechols
Hydroquinones
Hyperuricemia
Poisons
Phenols
Liver
Metabolic Activation
Hepatocellular Carcinoma
Japan
Wounds and Injuries
Therapeutics

Keywords

  • Benzbromarone
  • CYP
  • Hepatotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Strategic drug design to avoid the metabolic activation of hepatotoxic drugs. / Ohe, Tomoyuki; Takahashi, Kyoko; Nakamura, Shigeo; Mashino, Tadahiko.

In: Yakugaku Zasshi, Vol. 137, No. 3, 2017, p. 249-255.

Research output: Contribution to journalReview article

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