TY - JOUR T1 - Characterization of Eprinomectin <em>N</em>-Deacetylase in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 269 LP - 273 VL - 27 IS - 2 AU - Zhaopie Zeng AU - Nicholas W. Andrew Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/269.abstract N2 - The enzyme system responsible for theN-deacetylation of eprinomectin in rats was characterized. Tissue and subcellular studies showed that the hydrolysis activity was localized mainly in liver microsomes. ApparentKM and Vmaxvalues calculated from Lineweaver–Burk plots were 53 μM and 0.81 nmol/mg/min for male rats and 70 μM and 4.99 nmol/mg/min for female rats, respectively. Pretreatment of male rats with dexamethasone, phenobarbital, and pregnenolone 16α-carbonitrile increased the activity by more than 3-fold. Paraoxon and bis-4-nitrophenylphosphate strongly inhibited the deacetylase activity at concentrations as low as 1 μM. The hydrolysis activity also was inhibited by SKF525, but less effectively. Eserine strongly inhibited the activity at 1 × 10−4 M. HgCl2 decreased the activity to about 40% at a concentration of 1 × 10−4 M. FeCl3, CaCl2, MgCl2, and EDTA had little effect on the hydrolysis of eprinomectin, whereas NaF slightly increased the activity to 118%. Thus, the inhibition study suggested that eprinomectin deacetylase resembled “B” type carboxylesterase/amidases. The hydrolysis activity of eprinomectin and isocarboxazid, a specific substrate of RL2 [Hosokawa, M, Maki T and Satoh T (1987) Mol Pharmacol 31:579–584], by liver microsomes from rats treated with various cytochrome P-450 inducers correlated well (r = 0.92). Also, elusion profiles of esterase by gel filtration and ion exchange chromatography demonstrated that the active protein(s) for eprinomectin and isocarboxazid hydrolysis coeluted. Thus, RL2 or an enzyme system similar to RL2 is responsible for the N-deacetylation of eprinomectin. The American Society for Pharmacology and Experimental Therapeutics ER -