1,3-butadiene: cancer, mutations, and adducts. Part IV: Molecular dosimetry of 1,3-butadiene.

Analysis of N7-guanine adducts derived from 1,3-butadiene (BD) was conducted with use of liquid chromatography-mass spectrometry (LC-MS) in combination with stable isotope methods. The N7-guanine adducts were shown to undergo spontaneous depurination from DNA in vitro in both calf-thymus DNA and TK6-cell DNA. A comparison was made between BD-derived N7-guanine adduct concentrations both in liver DNA and urine of rats and mice exposed to BD. This has provided insight into the exposure of the animals to 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol), the three oxidative metabolites of BD thought to be responsible for BD-mediated carcinogenesis. The liver DNA of mice contained more of the two N7-guanine adducts of BDO--N7-2-hydroxy-3-butenyl-1-guanine (2HB1G) and N7-1-hydroxy-3-butenyl-2-guanine (1HB2G)--than the amounts in rats during the 10-day BD exposure and the 6 days after exposure that were monitored. An excess of 1HB2G over 2HB1G by a factor of approximately 10 in the rat liver and a factor of approximately 5 in the mouse liver was also observed. This regioselective difference was apparent during both the 10-day exposure and the 6 days after exposure. The half-lives of 2HB1G and 1HB2G were estimated as 4.3 days and 3.5 days, respectively, in the DNA of BD-exposed mice and rats. Higher amounts of 2HB1G and 1HB2G appeared in rat urine compared with mouse urine after the 10-day exposure to 1,250 ppm BD. Analysis of liver DNA for N7-guanine adducts derived from BDO2 revealed the presence of two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)-1-guanine (THBG). One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2 or BDO-diol, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2 or BDO-diol. There was more (+/-)-THBG and meso-THBG in liver DNA of mice compared with amounts in rats during the 10 days of BD exposure and the 6 days after exposure. A twofold excess of (+/-)-THBG over meso-THBG in rat liver was found at all of the time points monitored. After 10 days of exposure to BD, (+/-)-THBG in mouse liver was also present in an almost twofold excess over meso-THBG. At 6 days after exposure to BD, however, (+/-)-THBG and meso-THBG were present in almost equal amounts in mouse liver. Furthermore, amounts of the two THBG diastereomers in mouse liver 6 days after exposure to BD were almost fivefold greater than amounts in rat liver. The half-lives of (+/-)-THBG and meso-THBG appeared to be longer in mouse liver (4.1 days and 5.5 days, respectively) than in rat liver (3.6 days and 4.0 days, respectively). Higher amounts of (+/-)-THBG were excreted in rat urine compared with mouse urine. It is noteworthy that each of the N7-guanine adducts derived from BD was present in higher concentrations in the liver DNA of mice exposed to 1,250 ppm BD than in the liver DNA of rats exposed to the same dose. Conversely, each of the adducts was present in higher concentrations in the urine of rats compared with the urine of mice after exposure to 1,250 ppm BD.