Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide.
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide), an anticonvulsant agent, is primarily metabolized to 2-sulfamoylacetylphenol by reductive cleavage of the 1,2-benzisoxazole ring. Rabbit liver cytosol with an electron donor of aldehyde oxidase exhibited a significant zonisamide reductase activity that was sensitive to inhibition by menadione, an inhibitor of aldehyde oxidase. The result suggested that the cytosolic activity is caused by aldehyde oxidase, a cytosolic enzyme. In fact, rabbit and rat liver aldehyde oxidase had the ability to reduce zonisamide when supplemented with its electron donor. Apparent KM and Vmax values of aldehyde oxidase for zonisamide were 217 microM and 42 nmol/10 min/mg protein in the case of the rabbit liver enzyme, and 542 microM and 382 nmol/10 min/mg protein in the case of the rat liver enzyme, respectively. In rabbits, hamsters, mice, and guinea pigs, zonisamide reductase activity of the liver cytosols with 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, was much higher than that of the liver microsomes with NADPH. In rats, zonisamide reductase activity was examined with liver microsomes and cytosols from seven strains. The 2-hydroxypyrimidine-dependent cytosolic activity exhibited marked strain differences, unlike the NADPH-dependent microsomal activity. 1,2-Benzisoxazole was also reduced to salicylaldehyde by rabbit liver cytosol and aldehyde oxidase in the presence of 2-hydroxypyrimidine. Stoichiometric studies showed that 2-sulfamoylacetylphenol was formed accompanying nearly equimolar ammonia from zonisamide.
Sugihara
K
K
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
Kitamura
S
S
Tatsumi
K
K
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism*; D004579:Electron Transport; D006168:Guinea Pigs; D007555:Isoxazoles / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008647:Mesocricetus; D011743:Pyrimidines / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D011743:Pyrimidines; D000078305:Zonisamide; C041345:2-hydroxypyrimidine; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase