Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats.

Abstract Liver plays a central role in xenobiotics metabolism, thus affecting the in vivo disposition and therapeutic effects of drugs. Carboxylesterases (CESs), with the main isoforms CES1 and CES2, are important in the metabolism of ester-type prodrugs. However, influences of immunological liver injury on the activity of CES remain undefined. In the present study, we demonstrated treatment with lipopolysaccharide (LPS) suppressed the activities of CES1 and CES2. The decreased activities of CES1 and CES2 were preliminarily assessed by the hydrolysis assay for their common substrate p -nitrophenyl acetate (PNPA) with rat hepatic microsomal enzyme. Subsequently, RT-PCR results showed that the levels of CES1 mRNA and mRNA of CES2 (AB010635) and CES2 (AY034877) in the model group were significantly lower than those of the normal control group ( P P 0 -∞ and C max of imidaprilat were decreased from 2084.86 ± 340.66 ng · h − 1  · mL − 1 and 234.66 ± 68.85 ng · mL − 1 to 983.87 ± 315.34 ng · h − 1  · mL − 1 and 113.1 ± 19.69 ng · mL − 1 ( P 0 -∞ and C max of SN-38 were decreased from 8100 ± 918.6 ng · h − 1  · mL − 1 and 144.67 ± 20.28 ng · mL − 1 to 3270 ± 500.5 ng · h − 1  · mL − 1 and 56.19 ± 10.38 ng · mL − 1 ( P