Secondary Metabolism of Dinitrobenzyl Glucuronide Related to Production of Genotoxic Compounds of Dinitrotoluene in Male Wistar Rat

抄録

Urinary and biliary metabolites of male Wistar rats dosed orally with 2, 4-dinitrobenzyl glucuronide (2, 4-DNB-G) and 2, 6-dinitrobenzyl glucuronide (2, 6-DNB-G) which are major compounds excreted in bile after administration of carcinogenic 2, 4-dinitrotoluene (2, 4-DNT) and 2, 6-dinitrotoluene (2, 6-DNT) were examined by HPLC. The object of this study is to determine whether mutagenic 2, 4-dinitrobenzaldehyde (2, 4-DNBA1) and genotoxic 2-amino-6-nitrobenzyl alcohol (2A6NB) are produced in the secondary metabolism of 2, 4-DNB-G and 2, 6-DNB-G. Data from HPLC indicated that 2, 4-DNAB1 (about1%), in addition to 2, 4-DNB-G (about 8.6%), 2, 4-dinitrobenzyl alcohol (2, 4-DNB, about 0.1%), two aminonitrotoluenes (about 0.2%), two aminonitrobenzyl alcohols (about 0.1%), 4-acetylamino-2-nitrobenzoic acid (4AA2NBA, about 7.4%) and 4-acetylamino-2-aminobenzoic acid (4AA2ABA, about 1.8%) was excreted in the urine or bile after dosing 2, 4-DNB-G. This result, together with previous findings, indicates that 2, 4-DNBA1 is produced not only by oxidation of 2, 4-DNB formed from 2, 4-DNT, but by oxidation of 2, 4-DNB formed from 2, 4-DNB-G excreted in bile. In addtion, the formation of carcinogenic 2, 4-diaminotoluene (2, 4-DAT) was ascertained from the metabolic pathway of 2, 4-DNB-G based on the metabolites detected. No 2A6NB was found in the urine and bile after dosing 2, 6-DNB-G. However, 2-amino-6-nitrobenzoic acid (2A6NBA, about 0.2%), in addition to 2, 6-dinitrobenzyl alcohol (2, 6-DNB, <0.1%) and 2, 6-DNB-G (about 18%), was detected in the urine or bile after dosing 2, 6-DNB-G. This result, together with previous findings, indicates that 2A6NB is an intermediate in the production of 2A6NBA from 2, 6-DNB, and further suggests that the production of 2A6NB in the metabolism of 2, 6-DNT is coupled to the enterohepatic circulation of 2, 6-DNB. The results of this investigation suggest that the production of 2, 4-DNBA1 and 2, 4-DAT, and 2A6NB from 2, 4-DNB-G and 2, 6-DNB-G may play a role in the hepatocarcinogenicities of 2, 4-DNT and 2, 6-DNT.