Persistence of N7-(2,3,4-trihydroxybutyl)guanine adducts in the livers of mice and rats exposed to 1,3-butadiene

Liquid chromatography (LC) in combination with tandem mass spectrometry (MS /MS) and stable isotope methodology was employed for the analysis of the N7 -guanine (Gua) adducts derived from 1,2:3,4-diepoxybutane (BDO2) a reactive metabolite of 1,3-butadiene (BD). Two diastereomeric forms of N7-(2,3,4-tr ihydroxybutyl)guanine (THBG) were identified in the livers of both mice and rats. One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2, and the other diastereomer (meso-THBG) was formed by react ion of DNA with meso-BDO2. There was significantly more (+/-)-THBG and meso -THBG in the liver DNA of the mice when compared with those of the rats dur ing the 10 days of exposure to ED and the 6 days of postexposure that were monitored. There was a 2-fold excess of(+/-)-THBG over meso-THBG in the rat liver at all the time points. In the mouse liver after 10 days of exposure to ED, the (+/-)-THBG (3.9 adducts/10(6) normal bases) was also present in an almost 2-fold excess over meso-THBG (2.2 adducts/10(6) normal bases). H owever, B-days after exposure to ED, (+/-)THBG; (1.2 adducts/10(6) normal b ases) and meso-THBG (1.0 adduct/10(6) normal bases) were present in almost equal amounts in the mouse liver. Furthermore, there was an almost Ei-fold excess of the two THBG diastereomers in the mouse liver DNA 6 days after ex posure to ED when compared with rat liver DNA. The half-lives of(+/-)-THBG and meso-THBG appeared to be slightly longer in mouse liver (4.1 and 5.5 da ys, respectively) than in rat liver (3.6 and 4.0 days, respectively). The a pparent persistence of these adducts in the mouse may contribute to the inc reased susceptibility of this species to ED-induced carcinogenesis. It is p ossible that (+/-)-THBG and meso-THBG could have also been derived from the reaction of DNA with the hydrolysis product of BDO2, 1,2-dihydroxy-3,4-epo xybutane (DHEB). Surprisingly, a vast majority of the studies in which the mutagenic and carcinogenic potential of BDO2 have been examined have only e mployed the commercially available (+/-)-BDO2. In light of the present find ings, additional studies will be required to determine the potency of meso- BDO2 and the DHEB that is the precursor to meso-THBG as mutagens and carcin ogens.