DNA adducts formed from p-benzoquinone, an electrophilic metabolite of benzene, are extensively metabolized in vivo.
Benzetheno adducts derived from p-benzoquinone (p-BQ), a reactive metabolite of benzene, were reported to be formed by the reaction of p-BQ with DNA in vitro but have never been detected either in vivo or in experiments with living cells. Two of them, 3-hydroxy-3,N(4)-benzetheno-2'-deoxycytidine (DCBQ) and 7-hydroxy-1,N(2)-benzetheno-2'-deoxyguanosine (DGBQ), were administered to rats by single ip injections at the doses of 2 mg/kg each. The excretion of unchanged compounds DCBQ and DGBQ within 2 days amounted to 8.2 ± 1.9 and 4.5 ± 1.2% (mean ± SE) of the dose, respectively. Additionally, deribosylated metabolites of DCBQ and DGBQ, 3-hydroxy-3,N(4)-benzethenocytosine (CBQ) and 7-hydroxy-1,N(2)-benzethenoguanine (GBQ), were found amounting to 45.7 ± 10.2 and 2.9 ± 2.1% of the dose, respectively. An additional portion of CBQ and GBQ was liberated from their corresponding conjugates by acidic hydrolysis. Therefore, total recoveries of CBQ and GBQ in urine were 82.1 ± 13.5 and 11.6 ± 5.1% of the dose. To identify conjugated metabolites, DCBQ and DGBQ were administered intraperitoneally at the doses 10.5 and 11.0 mg/kg, respectively, to one animal each. Glucuronides of DCBQ, DGBQ, and GBQ as well as sulfates of DGBQ, CBQ, and GBQ were identified by ESI-LC-MS according to (M - H)(-) ions and their fragmentation. In addition, two oxygenated metabolites and their corresponding conjugates were detected for DGBQ and GBQ. One of these metabolites was identified as 2,7-dihydroxy-1,N(2)-benzethenoguanine OGBQ1. It coeluted with the product obtained by the reaction of HQ and p-BQ mixture with 8-hydroxy-2'-deoxyguanosine followed by acid hydrolysis. These findings suggest that both DCBQ and DGBQ undergo extensive biotransformation in vivo. CBQ appears to be the only p-BQ derived DNA adduct, which can be efficiently recovered from its conjugates and might be therefore useful in molecular dosimetry of benzene.
Department of Organic Chemistry, Faculty of Chemical Technology, Institute of Chemical Technology, Prague, Czech Republic. linharti@vscht.cz
Igor
I
Linhart
Petr
P
Mikes
Emil
E
Frantík
Jaroslav
J
Mráz
D000818:Animals; D001554:Benzene / Q000378:metabolism*; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D016227:Benzoquinones / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D007274:Injections, Intraperitoneal; D013058:Mass Spectrometry; D051381:Rats; D013997:Time Factors
D001562:Benzimidazoles; D016227:Benzoquinones; D018736:DNA Adducts; D003841:Deoxycytidine; D004247:DNA; D003849:Deoxyguanosine; D001554:Benzene