title: Identification of an unintended consequence of Nrf2-directed cytoprotection against a key tobacco carcinogen plus a counteracting chemopreventive intervention.
abstract: NF-E2-related factor 2 (Nrf2) is a major cytoprotective gene and is a key chemopreventive target against cancer and other diseases. Here we show that Nrf2 faces a dilemma in defense against 4-aminobiphenyl (ABP), a major human bladder carcinogen from tobacco smoke and other environmental sources. Although Nrf2 protected mouse liver against ABP (which is metabolically activated in liver), the bladder level of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP), the predominant ABP-DNA adduct formed in bladder cells and tissues, was markedly higher in Nrf2(+/+) mice than in Nrf2(-/-) mice after ABP exposure. Notably, Nrf2 protected bladder cells against ABP in vitro. Mechanistic investigations showed that the dichotomous effects of Nrf2 could be explained at least partly by upregulation of UDP-glucuronosyltransferase (UGT). Nrf2 promoted conjugation of ABP with glucuronic acid in the liver, increasing urinary excretion of the conjugate. Although glucuronidation of ABP and its metabolites is a detoxification process, these conjugates, which are excreted in urine, are known to be unstable in acidic urine, leading to delivery of the parent compounds to bladder. Hence, although higher liver UGT activity may protect the liver against ABP, it increases bladder exposure to ABP. These findings raise concerns of potential bladder toxicity when Nrf2-activating chemopreventive agents are used in humans exposed to ABP, especially in smokers. We further show that 5,6-dihydrocyclopenta[c][1,2]-dithiole-3(4H)-thione (CPDT) significantly inhibits dG-C8-ABP formation in bladder cells and tissues but does not seem to significantly modulate ABP-catalyzing UGT in liver. Thus, CPDT exemplifies a counteracting solution to the dilemma posed by Nrf2.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Paonessa
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Randall
authors.forename: Rex
authors.initials: R
authors.lastname: Munday
authors.forename: Dayana
authors.initials: D
authors.lastname: Argoti
authors.forename: Paul
authors.initials: P
authors.lastname: Vouros
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000611:Aminobiphenyl Compounds / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D018890:Chemoprevention; D019610:Cytoprotection; D018736:DNA Adducts / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004249:DNA Damage; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control
chemical_list: C522589:5,6-dihydrocyclopenta-1,2-dithiole-3-thione; D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; D051267:NF-E2-Related Factor 2; D013438:Sulfhydryl Compounds; D013871:Thiones; C006757:4-biphenylamine; D014453:Glucuronosyltransferase