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[Cancer Research 60, 5913-5915, November 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

NAD(P)H:Quinone Oxidoreductase 1 Deficiency Increases Susceptibility to Benzo(a)pyrene-induced Mouse Skin Carcinogenesis1

Delwin J. Long, II, Rebekah L. Waikel, Xiao-Jing Wang, Laszlo Perlaky, Dennis R. Roop and Anil K. Jaiswal2

Departments of Pharmacology [D. J. L., A. K. J.], Molecular and Cellular Biology [R. L. W., D. R. R.], Dermatology [X-J. W.], and Pediatrics [L. P.], Baylor College of Medicine, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that catalyzes the metabolic detoxification of quinones and their derivatives. This protects cells against quinone-induced oxidative stress, cytotoxicity, and mutagenicity. C57BL6 NQO1-/- mice, deficient in NQO1 RNA and protein, were generated in our laboratory. To investigate the role of NQO1 in chemical carcinogenesis, the dorsal skin of NQO1-deficient (NQO1-/-) and wild-type (NQO1+/+) mice were treated with a single dose of benzo(a)pyrene, followed by twice weekly applications of phorbol-12-myristate-13-acetate. The NQO1-/- mice showed a much higher frequency of skin tumor development when compared with their wild-type littermates. Interestingly, the male NQO1-/- mice were slower to develop skin tumors than their NQO1-/- female littermates. Histological analysis of the NQO1-/- tumors showed proliferative activity. These results demonstrate that NQO1 acts as an endogenous factor in protection against benzo(a)pyrene carcinogenicity.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
BP3 is an environmental pollutant and a major component of cigarette smoke. It is also a well-known rodent and human carcinogen (1) . BP is metabolically activated by cytochrome P-450 1A1 and epoxide hydrolase to >25 products (1 , 2) . This metabolic activation of BP is a prerequisite for BP mutagenicity and carcinogenicity.

NQO1 is a flavoprotein that catalyzes the two-electron reduction and detoxification of quinones, including BP quinones (3, 4, 5) . NQO1 gene expression is induced in response to xenobiotics, antioxidants, oxidants, heavy metals, UV light, and ionizing radiation (3, 4, 5, 6) . Interestingly, NQO1 is part of an electrophilic and/or oxidative stress-induced cellular defense mechanism that includes the induction of >24 genes (3, 4, 5, 6, 7) . Other genes that are coordinately induced with NQO1 include glutathione S-transferases, which conjugate hydrophobic electrophiles and reactive oxygen species with glutathione (6) , and {gamma}-glutamylcysteine synthetase, which plays a key role in the regulation of glutathione metabolism (7) . The coordinated induction of these genes, including NQO1, presumably provides the necessary protection for cells against free radical damage and oxidative stress. Previous studies have reported that many diverse chemicals (e.g., antioxidants and sulforaphane) block carcinogenesis (8 , 9) . The capacity of these chemicals to block carcinogenesis correlates with their capacity to induce detoxifying enzymes including NQO1. However, the individual role of NQO1 and other detoxifying enzymes in the prevention of chemical carcinogenesis remains unknown.

Recently, NQO1-/- mice were produced using targeted gene disruption (10) . Mice lacking a functional NQO1 gene (NQO1-/-) were born normal and reproduced the same as the wild-type NQO1+/+ mice. However, when treated with menadione, NQO1-/- mice exhibited increased oxidative stress and toxicity, as compared with the wild-type mice. The NQO1-/- mice are a model for NQO1 deficiency in humans and can be used to determine the role of this enzyme in protection from toxicity and carcinogenesis. To evaluate the possible role of NQO1 in protection against chemical carcinogenesis, we studied the sensitivity of NQO1-/- mice to BP-induced skin carcinogenesis.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Chemicals.
The BP and TPA were purchased from Sigma Chemical Co (St; Louis, MO). The 10% neutral-buffered formalin solution and acetone were purchased from Fischer Scientific (Houston, TX).

NQO1-/- and Wild-Type Mice.
C57BL6 NQO1-/- and wild-type mice were generated in our laboratory (10) . The animals were housed in polycarbonate cages in the animal facility, maintained with a 12-h light/dark cycle, a temperature of 24 ± 2o C, a relative humidity of 55 ± 10%, and a negative atmospheric pressure. The mice were fed with standard rodent chow and acidified tap water ad libitum for this study. Seven- to 9-week-old mice were used at the start of the experiment. Animals received humane care throughout the experiment according to the American Association of Laboratory Animal Care (AALAC) guidelines for animal welfare.

Experimental Protocol.
The backs of 7–9-week-old NQO1-/- and wild-type mice were shaved using hair clippers. The various concentrations (400, 800, or 1200 nmol) of BP were applied topically in acetone:NH4OH (1000:1). The control mice received the acetone:NH4OH alone. The mice then received twice weekly applications of 10 µg of TPA for 20 weeks starting 1 week after BP treatment.

Histological Examination.
The skin specimens were fixed in 4% neutral-buffered formalin solution and processed for paraffin embedding. Skin sections were prepared and placed on glass slides for H&E staining.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The basal NQO1 activities were determined in the skin, kidney, colon, liver, and lung in male and female wild-type and NQO1-/- mice by a procedure as described (3, 4, 5) . No significant differences were observed in NQO1 activity levels between male and female wild-type mice. Therefore, NQO1 data are shown only for male mice. NQO1 activities were 50 ± 5, 741 ± 44, 615 ± 37, 136 ± 10, and 74 ± 11 nmol of 2,6-dichlorophenolindophenol reduced/min/mg cytosolic protein (mean ± SE; n = 5) in the skin, kidney, colon, liver, and lung of wild-type mice. NQO1 activity was not detected in the skin, kidney, and colon of NQO1-/- mice. However, a small amount (>15% of wild-type) of NQO activity was detected in the liver and lung of the NQO1-/- mice. The values were 20 ± 4 and 6 ± 1 units in the liver and lung of NQO1-/- mice. Northern and Western analysis show no NQO1 RNA or protein expression in any of the studied tissues from NQO1-/- mice (data not shown). These results indicate that NQO1-/- mice are deficient in NQO1-RNA and NQO1-protein. The low level of NQO activity that is detected in the liver and lungs may be attributable to another isoenzymic form of NQO1. These results are supported by the observations of Radjendirane et al. (10) reported upon generation of the NQO1-/- mice.

The results of skin tumor induction by BP treatment are summarized in Table 1Citation . No tumors were observed in the wild-type (NQO1+/+) mice at a BP dose of 400 or 800 nmol (Table 1)Citation . Only 1 wild-type male mouse of 15 showed one papilloma 23 weeks after 1200 nmol (given one time) of BP initiation + TPA promotion (Table 1)Citation . In contrast, both male and female NQO1-/- mice showed significantly higher incidences of BP-induced skin tumors (Table 1)Citation . The differences were also observed with respect to time and frequency of tumor development between male and female NQO1-/- mice. Twenty % of the female mice developed skin tumors by the 19th week after BP treatment (Table 1)Citation . The frequency of tumors did not increase significantly with higher doses of BP at week 19. However, this response changed with the passage of time. Fifty % of the NQO1-/- female mice that had been treated with 800 and 1200 nmol of BP developed skin tumors by the 23rd week (Table 1)Citation . The male NQO1-/- mice developed BP-induced skin tumors slower, as compared with the NQO1-/- female mice. No skin tumors were observed in male NQO1-/- mice at week 19 with all three doses of BP and only 7% of the male NQO1-/- mice showed skin tumors at week 23 with a dose of 400 nmol of BP. The tumor frequency in male NQO1-/- mice increased to 20 and 33% with 800 and 1200 nmol of BP at week 23, respectively. The BP-induced tumor frequency in wild-type (NQO1+/+) and NQO1-/- mice observed at week 23 remained the same at week 31. Approximately 25% of the skin tumors converted to aggressively growing carcinomas in the NQO1-/- mice. The skin tumors found in the NQO1-/- mice were classified histologically as epithelial in origin, and a typical carcinoma is shown (Fig. 1)Citation . In the similar experiment, the treatment of wild-type and NQO1-/- mice with TPA alone did not demonstrate tumor development. These results demonstrate that an NQO1-deficient condition increases the sensitivity to BP carcinogenesis.


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  		Table 1 Mouse skin tumors developed after a single topical application of BP

Seven- to 9-week-old C57BL6 (wild-type and NQO1-/-) mice were shaved on their backs, and a single dose of BP was topically applied, followed by twice weekly applications of TPA. Ten µg of TPA were used in a single application. The mice were compared at weeks 19, 23, and 31. The frequency of tumors observed at week 31 was the same as week 23, and 25% of tumors converted to malignant carcinomas. Similar experiments with BP or TPA alone did not produce skin tumors in wild-type and NQO1-/- mice.

 


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  		Fig. 1. Phenotype and histotype of a typical NQO1-/- tumor induced by 800 nmol of BP. A, gross appearance of a skin tumor, which developed in a NQO1-/- mouse. The concave nature of this tumor is highly suggestive of malignancy. B, histotype of this tumor (A) reveals a poorly differentiated squamous cell carcinoma with a focal area of spindle cell squamous cell carcinoma (SP). KP, keratin pearl. Bar, 100 mm.

 
The metabolic activation of BP is a prerequisite for its carcinogenic effect (1 , 2) . BP is metabolized by CYP1A1 and related enzymes into more than 24 reactive metabolites. This includes the highly cytotoxic, mutagenic, and carcinogenic benzo(a)pyrene-7,8-diol-9,10-epoxide (11) . Also included among these metabolites are the benzo(a)pyrene-6,12-quinones, 1,6-quinones, and 3,6quinones (1) . BP quinones are further activated by one-electron reducing enzymes such as cytochrome P-450 reductase, leading to the production of reactive oxygen species. This results in oxidative stress and related adverse effects. Therefore, BP quinones are known to inhibit DNA synthesis and are highly toxic to Syrian hamster embryo cultures (12) . BP quinones are also known to form DNA adducts (13) and are mutagenic to an oxidation sensitive strain of Salmonella (14) . In a single study, BP quinones produced a low frequency of skin tumors in wild-type CD-1 mice (15) . NQO1 is known to compete with cytochrome P-450 reductase and catalyze two-electron reduction and detoxification of BP quinones (13) . This prevents the formation of highly reactive quinone metabolites and significantly reduces BP- and BP quinone-induced DNA adduct formation and mutagenicity (13 , 16) . Therefore, it is expected that NQO1 protection against BP carcinogenicity in wild-type mice may be related to its capacity to detoxify BP quinones and prevent the generation of highly reactive quinone metabolites. The loss of NQO1 in NQO1-/- mice may have led to the accumulation of BP quinones that helped generate tumors through a cytotoxic or promotional stimulation. However, it is possible that NQO1 detoxifies BP metabolites other than BP quinones, leading to the increased protection against BP carcinogenicity. Further studies are being done to understand the mechanism of protective effect of NQO1. The mechanism of differences between male and female NQO1-/- mice susceptibility to BP-induced skin tumors remains unknown. The sexual dimorphism has been reported earlier for 7,12-dimethylbenz[a]anthracene initiated and mirexpromoted papillomas in mice (17) . It was shown that 7,12-dimethylbenz[a]anthracene + mirex-treated female mice were more sensitive to develop papillomas than male mice. This observation was similar as observed in the present studies. It was also shown that ovarian hormones were responsible for the increased sensitivity of female mice to the skin tumor-promoting ability of mirex (17) . The differences in response to BP-initiated and TPApromoted tumors between male and female NQO1-/- mice in the present study may or may not be related to the differences in sex hormones. The sex differences may be at the level of BP-induced initiation or TPA promotion.

The human NQO1 gene has been localized to chromosome 16q22 (18) . Recent studies have identified a C->T mutation in the NQO1 gene that resulted in a proline-to-serine change and the loss of NQO1 activity (19) . Two to 4% of the human populations worldwide carry both mutant alleles and are deficient in NQO1. The present studies on increased sensitivity of NQO1-/- mice to BP carcinogenicity demonstrate that these human individuals might have an increased risk to BP carcinogenicity. NQO1 may also protect against chemicals other than BP. This hypothesis is supported by recent observations that individuals carrying mutant alleles of NQO1 are more susceptible to benzene and benzene metabolite toxicity and leukemia (20 , 21) .

NQO1 activity is ubiquitously present in all tissues types (3, 4, 5) . Several investigators have observed large variations in NQO1 activity among different individuals, tissue types of the same individual, and between normal and tumor tissues (3, 4, 5) . Tumor tissues and cells of hepatic and colonic origin express higher levels of NQO1, as compared with normal tissues and cells of similar origins (4 , 5) . The normal tissues that surround the hepatic tumors also express higher levels of the NQO1 gene, presumably to play an unknown role in tumor progression (4 , 5) .

The present study demonstrates that NQO1 is an endogenous protector against BP-induced carcinogenicity. It is rational to suggest that this protection may be attributable to NQO1-catalyzed detoxification of BP quinones and prevention of reactive oxygen species generation. However, it may also involve NQO1-catalyzed detoxification of other metabolites of BP. The mechanism of increased susceptibility to BP-induced skin tumors in NQO1-/- mice remains to be investigated.


   ACKNOWLEDGMENTS
 
We are thankful to our colleagues for helpful discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by NIH Grant RO1 ES07943. Back

2 To whom requests for reprints should be addressed, at Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-7691; Fax: (713) 798-3145; E-mail: ajaiswal{at}bcm.tmc.edu Back

3 The abbreviations used are: BP, benzo(a)pyrene; NQO1, NAD(P)H:quinone oxidoreductase 1; TPA, phorbol-12-myristate-13-acetate. Back

Received 6/ 9/00. Accepted 9/14/00.


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 Materials and Methods
 Results and Discussion
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From the Cover: Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice
PNAS, March 13, 2001; 98(6): 3410 - 3415.
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G. C. Yeh, P. J. Daschner, J. Lopaczynska, C. J. MacDonald, and H. P. Ciolino
Modulation of Glucose-6-phosphate Dehydrogenase Activity and Expression Is Associated with Aryl Hydrocarbon Resistance in Vitro
J. Biol. Chem., September 7, 2001; 276(37): 34708 - 34713.
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R. I. Bello, C. Gomez-Diaz, F. Navarro, F. J. Alcain, and J. M. Villalba
Expression of NAD(P)H:Quinone Oxidoreductase 1 in HeLa Cells. ROLE OF HYDROGEN PEROXIDE AND GROWTH PHASE
J. Biol. Chem., November 21, 2001; 276(48): 44379 - 44384.
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