title: Toxicological potential of acyl glucuronides and its assessment.
abstract: Idiosyncratic drug toxicity (IDT) is a serious problem in drug development. Reactive metabolites are postulated to be one of the causes for IDT. Conjugated metabolites are generally non-reactive except for acyl glucuronides (AGs), which are sufficiently reactive to covalently bind to endogenous proteins. Thus, it has been suggested that AGs would contribute to IDT caused by carboxylic acid-containing drugs. Glucuronidation of a carboxylate residue is catalyzed by UDP-glucuronosyltransferase 1A and 2B isoforms. Unstable AGs undergo intramolecular rearrangements as well as non-enzymatic and enzymatic hydrolysis. The instability and reactivity toward proteins have been well studied for a large number of AGs. Moreover, the half-life of AGs in neutral buffer is becoming a common marker for the prediction of toxicity caused by carboxylic acid-containing drugs in the screening of new chemical entities; however, the underlying mechanisms of the toxicity are not elucidated. Recently, an immunostimulation assay has been proposed for the assessment of the toxicological potential of AGs, which may have a better predictability compared with half-life and peptide adduct assays. In addition to in vitro studies, studies in model animals indicate the in vivo toxicological potential of AGs and help understand the mechanisms of the AG toxicity.
authors.affiliation: DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda 335-8505, Japan. Electronic address: Iwamura.Atsushi@mf.mt-pharma.co.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwamura
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D020719:Glucuronides / Q000633:toxicity*; D006801:Humans
chemical_list: D020719:Glucuronides
keywords: Acyl glucuronide; Drug development; Drug toxicity; Immune activation; In vitro screening; In vivo model; Protein adduct; Reactive metabolite; UDP-glucuronosyltransferase