title: Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver.
abstract: Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil (MMF), is primarily metabolized by glucuronidation to a phenolic glucuronide (MPAG) and an acyl glucuronide (AcMPAG). It is known that AcMPAG, which may be an immunotoxic metabolite, is deglucuronidated in human liver. However, it has been reported that recombinant β-glucuronidase does not catalyze this reaction. AcMPAG deglucuronidation activity was detected in both human liver cytosol (HLC) and microsomes (HLM). In this study, the enzyme responsible for AcMPAG deglucuronidation was identified by purification from HLC with column chromatographic purification steps. The purified enzyme was identified as α/β hydrolase domain containing 10 (ABHD10) by amino acid sequence analysis. Recombinant ABHD10 expressed in Sf9 cells efficiently deglucuronidated AcMPAG with a K(m) value of 100.7 ± 10.2 μM, which was similar to those in HLM, HLC, and human liver homogenates (HLH). Immunoblot analysis revealed ABHD10 protein expression in both HLC and HLM. The AcMPAG deglucuronidation by recombinant ABHD10, HLC, and HLH were potently inhibited by AgNO(3), CdCl(2), CuCl(2), PMSF, bis-p-nitrophenylphosphate, and DTNB. The CL(int) value of AcMPAG formation from MPA, which was catalyzed by human UGT2B7, in HLH was increased by 1.8-fold in the presence of PMSF. Thus, human ABHD10 would affect the formation of AcMPAG, the immunotoxic metabolite.
authors.affiliation: Department of Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwamura
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Ryota
authors.initials: R
authors.lastname: Higuchi
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D004950:Esterases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D020719:Glucuronides; C113145:mycophenolic acid glucuronide; D004950:Esterases; C572634:ABHD10 protein, human; D009173:Mycophenolic Acid