Among numerous adducts formed by reaction of DNA with p-benzoquinone (p-BQ), an electrophilic metabolite of benzene, only N2-(4-hydroxyphenyl)guanine (N2HPG) has been confirmed in vivo. If excreted in urine N2HPG would be a candidate non-invasive biomarker of the DNA damage caused by benzene. To test this hypothesis, biotransformation of N2HPG was studied in rats. Unchanged N2HPG in urine amounted to 8.0 ± 2.2% and 9.1 ± 1.7% (mean ± SE) at the dose of 2 mg/kg excreted within 1 and 2 days after ip dosage, respectively. After acidic hydrolysis of the urine a slight but consistent increase in urinary N2HPG to 9.5 ± 3.2% and 11 ± 2.6% of dose was found within 1 and 2 days, respectively, indicating formation of hydrolysable conjugates. An oxidised metabolite was detected by LC-ESI-MS and identified by comparison with authentic standard as N2-(4-hydroxyphenyl)-8-oxoguanine (N2HPOG). Its excretion amounted to 2.7 ± 0.2% of dose and increased to 12.0 ± 2.7% of dose when N2HPOG was released from its conjugates by acidic hydrolysis. Glucuronides and sulphates of both N2HPG and N2HPOG were confirmed in urine by LC-ESI-MS and by enzymatic treatment with glucuronidase/sulphatase. These results indicate an extensive metabolism of N2HPG in vivo, which must be taken into account when considering N2HPG as a possible biomarker of exposure to benzene.

Department of Organic Chemistry Faculty of Chemical Technology Institute of Chemical Technology Prague Technická 1905 CZ 166 28 Prague Czech Republic

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