RT Journal Article
SR Electronic
T1 Interindividual Variability of Carboxymethylenebutenolidase Homolog, a Novel Olmesartan Medoxomil Hydrolase, in Human Liver and Intestine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.113.051482
DO 10.1124/dmd.113.051482
A1 Tomoko Ishizuka
A1 Veronika Rozehnal
A1 Thomas Fischer
A1 Ayako Kato
A1 Seiko Endo
A1 Yasushi Yoshigae
A1 Atsushi Kurihara
A1 Takashi Izumi
YR 2013
UL http://dmd.aspetjournals.org/content/early/2013/03/07/dmd.113.051482.abstract
AB 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 wildtype protein although no minor allele was genotyped in the 40 individual liver specimens.