Relationship between CES2 genetic variations and rifampicin metabolism

Objectives: Rifampicin is known to be deacetylated in vivo, resulting in its metabolite 25-desacetyl rifampicin, but the enzyme metabolizing rifampicin and the association of this process with any genetic variation have not yet been elucidated. In this study, genetic variations of a surrogate enzyme, carboxylesterase 2 (CES2), and their association with the metabolism of this drug, were investigated. Methods: Plasma concentrations of rifampicin and 25-desacetyl rifampicin were measured in 35 patients with tuberculosis receiving a first-line antituberculosis treatment. Direct PCR-based sequencing of the CES2 gene, covering all 12 exons, the 5′-untranslated region (UTR), the 3′-UTR and intronic and promoter regions, was per-formed. A dual luciferase reporter assay was carried out to assess whether variations in the promoter region affected the transcription of this gene. Results: Ten variations were detected, of which two were in the candidate promoter region, five in introns and three in the 3′-UTR. One of the variations in the 3′-UTR was a novel variation. Genotypes at three closely linked variations (c.22263A.G, c.269-965A.G and c.1612+136G.A) and c.1872*302_304delGAA were associated with significantly different plasma rifampicin concentrations. The mean plasma rifampicin concentration signifi-cantly increased with the number of risk alleles at the three closely linked variations, while the plasma concen-tration decreased along with an increase in the number of risk alleles at c.1872*302_304delGAA. When HepG