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J.Health Sci., 46(5), 329-335, 2000
Secondary Metabolism of Dinitrobenzyl Glucuronide Related to Production of Genotoxic Compounds of Dinitrotoluene in Male Wistar Rat
Masa-aki Mori,*, a Miki Shoji,b Michio Sayama,c Takashi Kondo,b Masami Inoue,c and Ken-ichi Kodairac
aSchool of Health Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, bFaculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan, and cFaculty of Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555, Japan
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-DNBAl) 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-DNBAl (about 1%), 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-DNBAl 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 addition, 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-DNBAl 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.
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