1,3-butadiene (BD) is a known human carcinogen found in the polymer industry, tobacco smoke, and urban air. BD is metabolically activated to electrophilic metabolite, 3,4-epoxy-1-butene (EB). EB is detoxified through glutathione conjugation and the mercapturic acid pathway to form monohydroxy-3-butenyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA). If not detoxified, EB can react with guanine bases of DNA to form N7-(1-hydroxyl-3-buten-1-yl) guanine (EB-GII) adducts. Both MHBMA and EB-GII are associated with smoking, decreasing by 80% and 34% respectively post-smoking cessation. In contrast, urinary DHBMA levels remain unchanged post-smoking cessation, suggesting that they can originate from endogenous sources. To quantify the contributions of endogenous MHBMA, DHBMA, and EB-GII to the overall MHBMA, DHBMA, and EB-GII levels, Sprague-Dawley rats were exposed to low ppm levels of isotopically labeled BD (BD -d6 , 0, 0.3, 0.5, and 3 ppm) for 6 h/day for 7 days. Following treatment, urine and target tissues (liver, pancreas, heart, lung, mammary glands, and blood) were collected. Metabolites and adducts resulting from BD-d6 exposure carry a deuterium isotope label, while endogenous metabolites and adducts are unlabeled and can be distinguished by mass spectrometry. A dose-dependent increase in MHBMA-d6, DHBMA-d5, and EB-GII-d6 was observed in urine of rats exposed to BD-d6. In addition, endogenous MHBMA, DHBMA, and EB-GII were observed in most samples and were unaffected by BD-d6 exposure. Following treatment with 3 ppm BD-d6, the levels of exogenous urinary MHBMA and EB-GII were far more prevalent than the concentrations of endogenous metabolites and adducts, suggesting that butadiene exposure was the main source of these species. In contrast, the concentrations of exogenous DHBMA were only 2.5-fold higher than that of the endogenous metabolite. This is consistent with previous studies that have shown significant amounts of DHBMA that could not be explained by BD exposures. A dose-dependent increase in genomic EB-GII-d6 was observed in the liver of rats exposed to BD-d6 in addition to endogenous levels of EB-GII that were not affected by BD-d6 exposure. Our results indicate that following sub ppm exposures to BD as experienced by smokers and city residents, endogenous sources have a major impact on the total levels of MHBMA, DHBMA, and EB-GII. Our ongoing studies aim to reveal the metabolic/dietary sources of these adducts.

Endogenous versus exogenous sources of monohydroxy-3-butenyl and dihydroxybutyl mercapturic acid metabolites and N7-(1-hydroxy-3-buten-2-yl) guanine DNA adducts

ACS Fall 2021

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