Identification of an Unintended Consequence of Nrf2-Directed Cytoprotection against a Key Tobacco Carcinogen plus a Counteracting Chemopreventive Intervention

Abstract

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. While 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. While 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, while 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 demonstrate 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 appear to significantly modulate ABP-catalyzing UGT in liver. Thus, CPDT exemplifies a counteracting solution to the dilemma posed by Nrf2.

The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage

“…Our finding that this liver factor is potentially suppressed by androgen but is not affected by estrogen may facilitate the search for it. We have previously shown that knockout of Nrf2, a major regulator of cytoprotective and drug-metabolizing genes, reduces the level of dG-C8-ABP in the bladder but increases its level in the liver in mice treated with ABP [33]. Thus, androgen and Nrf2 seem to behave similarly with regard to modulating bladder and liver susceptibility to ABP.…”

Olmesartan ameliorates urinary dysfunction in the spontaneously hypertensive rat via recovering bladder blood flow and decreasing oxidative stress

“…The antioxidant system is mediated by Nrf2, and its mediated cytoprotection is essential in defending cells or organs against cancer, neurodegenerative disease, aging, cardiovascular disease, and pulmonary fibrosis . Also, it is known that Nrf2 is a major cytoprotective gene and is a key chemopreventive target against cancer or toxic damage in the bladder . Previous reports showed that Nrf2 protects human bladder urothelial cells and alveolar epithelial cells against the toxic or virus induced injuries .…”

A Perspective on Dietary Phytochemicals and Cancer Chemoprevention: Oxidative Stress, Nrf2, and Epigenomics

“…It has been demonstrated that Nrf2 upregulates UGT activity and promotes a conjugation reaction of 4-aminobiphenyl (ABP) from tobacco smoke with glucuronic acid in the liver, which might protect the liver against ABP [99]. The GST activity was reduced in the liver and small intestine of Nrf2 KO mice, and oltipraz, a chemopreventive agent, does not affect the expression levels of these enzymes in Nrf2-KO mice compared with wild-type mice [100].…”

“…It has been reported that the disruption of NQO1 contributed to a higher susceptibility to B[ a ]P-induced skin carcinogenesis in mice [103]. Lower Nqo1 expression and activity were found in the liver, small intestine, and forestomach of Nrf2-KO mice [75, 99, 100]. Early carcinogenesis induced by cyclophosphamide, which causes oxidative stress in the rat liver, can be effectively inhibited by the powerful antioxidant astaxanthin accompanied by an increase in NQO-1 and HO-1 as mediated through the Nrf2-ARE pathway [104].…”