Arylacetamide deacetylase activity towards monoacetyldapsone : Species comparison, factors that influence activity, and comparison with 2-acetylaminofluorene and p-nitrophenyl acetate hydrolysis
Abstract The deacetylation of monoacetyldapsone (MADDS) was examined in liver microsomes and cytosol from male Sprague-Dawley rats, Golden Syrian hamsters, and Swiss Albino mice. All three rodent species demonstrated greater MADDS deacetylation activity in liver microsomes than in liver cytosol. Further investigations were conducted in hamsters. The velocity of MADDS deacetylation in major organs in the hamster was greatest in the intestine, followed by the liver and kidney. The effect of pretreatment with common inducers on liver microsomal deacetylation activity was also examined in the hamster. Phenobarbital, 100 mg/kg/day × 3 days, did not alter activity, while dexamethasone at the same dose reduced 2-acetylaminofluorene (2-AFF), MADDS, and p -nitrophenyl acetate (NPA) hydrolysis by at least 50%. Due to a previous report that KI activated the deacetylation of an arylacetamide in vitro (Khanna et al ., J Pharmacol Exp Ther 262 : 1225–1231, 1992), the effects of the halides KF, KCl, KBr and KI on MADDS hydrolysis in vitro were tested. Of the halides studied, only KF altered MADDS hydrolysis, resulting in an almost complete inhibition of deacetylase activity at 50 mM (with the initial concentration of MADDS at 0.6 mM) with an IC 50 = 0.16 mM. Cornish-Bowden and Dixon plots indicated that the inhibition exerted by KF was non-competitive. The rank order of inhibitor potencies was constructed using phenylmethylsulfonyl fluoride (PMSF), bis ( p -nitrophenyl)phosphate (BNPP), physostigmine, and KF with 2-AFF, MADDS, and NPA as substrates. Different rank order potencies were obtained for each of the substrates tested. The substrates 2-AFF, MADDS, and NPA did not act as competitive inhibitors on the hydrolysis rates of each other. Liver microsomal arylacetamide deacetylase activity was greater in male hamsters than in females with either MADDS or 2-AAF as substrates; however, hydrolysis of NPA was similar in both male and female hamsters. These data support the hypothesis that the enzyme which catalyzes the hydrolysis of MADDS differs from that catalyzing either 2-AAF or NPA hydrolysis.
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