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

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概要

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• 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.

• 公益社団法人日本薬学会の論文
• 2000-10-01

著者

• Inoue Makoto

  名古屋市立大学 薬研究生薬学

• Inoue M

  Lab. Of Medicinal Resources School Of Pharmacy Aichi Gakuin Univ.

• Inoue Masami

  Faculty Of Engineering Toyama University

• Inoue M

  Laboratory Of Pharmacognosy Graduate School Of Pharmaceutical Sciences Nagoya City University

• MORI Masa-aki

  Department of Health Sciences, School of Medicine, Kyushu University

• Inoue M

  Nagoya‐city Univ. Aichi Jpn

• Mori Masa-aki

  Department Of Health Sciences School Of Medicine Kyushu University

• Sayama M

  Department Of Material Systems Engineering And Life Science Faculty Of Engineering Toyama University

• Sayama Michio

  Faculty Of Engineering Toyama University

• Mori Masa-aki

  School of Health Sciences, Kyushu University

• Shoji Miki

  Faculty of Medicine, Toyama Medical and Pharmaceutical University

• Kondo Takashi

  Faculty of Medicine, Toyama Medical and Pharmaceutical University

• Kodaira Ken-ichi

  Faculty of Engineering, Toyama University

• Shoji Miki

  Faculty Of Medicine Toyama Medical And Pharmaceutical University

• Kodaira Ken-ichi

  Faculty Of Engineering Toyama University

• Kondo Takashi

  Faculty Of Medicine Toyama Medical And Pharmaceutical University

• Kondo Takashi

  Faculty Of Agriculture Mie University

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