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.
Highlights
NF-E2–related factor 2 (Nrf2) is a ubiquitous transcription factor that stimulates the expression of genes involved in many aspects of cytoprotection, most notably those for phase 2 enzymes, such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase-1 (NQO1) and UDP-glucuronosyltransferase (UGT)
Male C57BL/6 mice (6–8 weeks of age, both wild-type and Nrf2 knockout) were given a single i.p. dose of ABP at 10 and 50 mg/kg; 24 hours later, ABP–DNA adduct levels in bladder tissues were measured. dG-C8-ABP, which accounts for 80% of all ABP–DNA adducts formed in human bladder tissues in vivo [22, 23], was quantified by capillary liquid chromatography and nanoelectrospray ionization–MS-MS
We previously showed that ABP and its metabolite N-OH-AABP caused significant dG-C8-ABP formation in human bladder RT4 cells and other cells in vitro [16]
Summary
NF-E2–related factor 2 (Nrf2) is a ubiquitous transcription factor that stimulates the expression of genes involved in many aspects of cytoprotection, most notably those for phase 2 enzymes, such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase-1 (NQO1) and UDP-glucuronosyltransferase (UGT). Phase 2 enzymes catalyze detoxification reactions of carcinogens and oxidants and thereby play important roles in prevention of cancer and other diseases. Authors' Affiliations: 1Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York; 2Barnett Institute, Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts; and 3AgResearch, Ruakura Research Center, Hamilton, New Zealand.
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