title: Interindividual variability of carboxymethylenebutenolidase homolog, a novel olmesartan medoxomil hydrolase, in the human liver and intestine.
abstract: Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor antagonist. OM is rapidly converted into its active metabolite olmesartan by multiple hydrolases in humans, and we recently identified carboxymethylenebutenolidase homolog (CMBL) as one of the OM bioactivating hydrolases. In the present study, we further investigated the interindividual variability of mRNA and protein expression of CMBL and OM-hydrolase activity using 40 individual human liver and 30 intestinal specimens. In the intestinal samples, OM-hydrolase activity strongly correlated with the CMBL protein expression, clearly indicating that CMBL is a major contributor to the prodrug bioactivation in human intestine. The protein and activity were highly distributed in the proximal region (duodenum and jejunum) and decreased to the distal region of the intestine. Although there was high interindividual variability (16-fold) in both the protein and activity in the intestinal segments from the duodenum to colon, the interindividual variability in the duodenum and jejunum was relatively small (3.0- and 2.4-fold, respectively). In the liver samples, the interindividual variability in the protein and activity was 4.1- and 6.8-fold, respectively. No sex differences in the protein and activity were shown in the human liver or intestine. A genetically engineered Y155C mutant of CMBL, which was caused by a single nucleotide polymorphism rs35489000, showed significantly lower OM-hydrolase activity than the wild-type protein although no minor allele was genotyped in the 40 individual liver specimens.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. ishizuka.tomoko.xx@daiichisankyo.co.jp
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Veronika
authors.initials: V
authors.lastname: Rozehnal
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.forename: Ayako
authors.initials: A
authors.lastname: Kato
authors.forename: Seiko
authors.initials: S
authors.lastname: Endo
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshigae
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005260:Female; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D002265:Carboxylic Ester Hydrolases; C046130:carboxymethylenebutenolidase