METABOLISM OF 2,6-DINITRO[3-H-3]TOLUENE BY HUMAN AND RAT-LIVER MICROSOMAL AND CYTOSOLIC FRACTIONS

被引:7
作者
CHAPMAN, DE
MICHENER, SR
POWIS, G
机构
[1] UNIV ARIZONA,ARIZONA CANC CTR,1501 N CAMPBELL AVE,TUCSON,AZ 85724
[2] MAYO CLIN & MAYO FDN,DEPT PHARMACOL,ROCHESTER,MN 55905
关键词
D O I
10.3109/00498259209049907
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. 2,6-Dinitrotoluene (2,6-DNT) metabolism by human liver and male Fischer F344 rat liver subcellular fractions under aerobic (100% oxygen) and anaerobic (100% nitrogen) incubation conditions was examined. Under aerobic conditions the major 2,6-DNT metabolite formed by hepatic microsomes was 2,6-dinitrobenzyl alcohol (2,6-DNBalc); under anaerobic conditions 2-amino-6-nitrotoluene (2Am6NT) was the major metabolite. 2. Rates of 2,6-DNBalc formation by human and rat liver microsomes under aerobic conditions were 247 and 132 pmol/min per mg protein, respectively. Rates of 2Am6NT formation by human and rat liver microsomes under anaerobic conditions were 292 and 285 pmol/min per mg protein, respectively. Anaerobic reduction of 2,6-DNT to 2Am6NT by rat and human liver microsomes was inhibited by carbon monoxide and metyrapone, which indicates that microsomal metabolism of 2,6-DNT to 2Am6NT is mediated by cytochrome P-450. 3. Liver cytosolic fractions also metabolized 2,6-DNT to 2Am6NT under anaerobic conditions. Formation of 2Am6NT by human and rat liver cytosols was supported by hypoxanthine, NADPH and NADH. Allopurinol inhibited the hypoxanthine-supported anaerobic metabolism of 2,6-DNT by rat, but not human, liver cytosol. Dicumarol inhibited the NADPH-supported anaerobic metabolism of 2,6-DNT by human, but not rat, liver cytosol. These results indicate that xanthine oxidase contributes to the hypoxanthine-supported anaerobic metabolism of 2,6-DNT by human liver cytosol.
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页码:1015 / 1028
页数:14
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