318 Chem. Res. Toxicol., Vol. 14, No. 3, 2001
Lakshmi et al.
(17) Lakshmi, V. M., Bell, D. A., Watson, M. A., Zenser, T. V., and
Davis, B. B. (1995) N-Acetylbenzidine and N,N′-diacetylbenzidine
formation by rat and human liver slices exposed to benzidine.
Carcinogenesis 16, 1565-1571.
(18) Rothman, N., Talaska, G., Hayes, R., Bhatnagar, V., Bell, D.,
Lakshmi, V., Kashyap, S., Dosemeci, M., Kashyap, R., Hsu, F.,
J aeger, M., Hirvonen, A., Parikh, D., Davis, B., and Zenser, T.
(1997) Acidic urine pH is associated with elevated levels of free
urinary benzidine and N-acetylbenzidine and urothelial cell DNA
adducts in exposed workers. Cancer Epidemiol., Biomarkers Prev.
6, 1039-1042.
ated to 4-aminobiphenyl, a bladder carcinogen (36).
AABP and 4′-OH-AABP have been reported in urine from
animals treated with 4-aminobiphenyl (32). In vivo
results demonstrating deamination of benzidine (34, 35)
suggest that nitrosation reactions similar to those re-
ported here will be demonstrated for benzidine with
corresponding products 4-aminobiphenyl and 4-OH-ami-
nobiphenyl. Thus, the reactions reported here are likely
to occur in vivo, and represent new pathways for me-
tabolism and activation of aromatic amine carcinogens.
(19) Beckman, J . S., Chen, J ., Ischiropoulos, H., and Crow, J . P. (1994)
Oxidative chemistry of peroxynitrite. Methods Enzymol. 233,
229-240.
Ack n ow led gm en t. We thank Priscilla DeHaven and
Cindee Rettke for excellent technical assistance. This
work was supported by the Department of Veterans
Affairs (T.V.Z.) and National Cancer Institute Grant
CA72613 (T.V.Z.). Mass spectrometry was performed at
the Mass Spectrometry Resource Center, Washington
University School of Medicine, through NIH Grants RR-
00954 and AM-20579. H NMR analysis was performed
by Dr. Narayana Mysore, Shell Chemicals, subsidiary of
Shell Oil Company, Houston, TX.
(20) NIH Guidelines for the Laboratory Use of Chemical Carcinogens
(1981) NIH Publication 81-2385, U.S. Government Printing Office,
Washington, DC.
(21) Babior, B. M., Kipnes, R. S., and Curnutte, J . T. (1973) Biological
defense mechanisms. The production by leukocytes of superoxide,
a potential bactericidal agent. J . Clin. Invest. 52, 741-744.
(22) Lakshmi, V. M., Hsu, F. F., McGarry, A. E., Davis, B. B., and
Zenser, T. V. (2000) Hypochlorous acid-mediated activation of
N-acetylbenzidine to form N′-(3′-monophospho-deoxyguanosin-8-
yl)-N-acetylbenzidine. Toxicol. Sci. 53, 202-212.
(23) van der Vliet, A., Eiserich, J . P., Halliwell, B., and Cross, C. E.
(1997) Formation of reactive nitrogen species during peroxidase-
catalyzed oxidation of nitrite. J . Biol. Chem. 272, 7617-7625.
(24) Eiserich, J . P., Cross, C. E., J ones, A. D., Halliwell, B., and van
der Vliet, A. (1996) Formation of nitrating and chlorinating
species by reaction of nitrite with hypochlorous acid. J . Biol.
Chem. 271, 19199-19208.
(25) Wink, D. A., Cook, J . A., Kim, S. Y., Vodovotz, Y., Pacelli, R.,
Krishna, M. C., Russo, A., Mitchell, J . B., J ourd’Heuil, D., Miles,
A. M., and Grishham, M. B. (1997) Superoxide modulates the
oxidation and nitrosation of thiols by nitric oxide-derived reactive
intermediates. J . Biol. Chem. 272, 11147-11151.
1
Refer en ces
(1) Parsonnet, J . (1999) Microbes and Malignancy. Infection as a
Cause of Human Cancer, Oxford University Press, New York.
(2) Pisani, P., Parking, D. M., Munoz, N., and Ferlay, J . (1997) Cancer
and infection: Estimates of the attributable fraction in 1990.
Cancer Epidemiol. Rev. 6, 387-400.
(3) Bejany, D. E., Lockhart, J . L., and Rhamy, R. K. (1987) Malignant
vesical tumors following spinal cord injury. J . Urol. 138, 1390-
1392.
(26) Santos, C. X. C., Bonini, M. G., and Augusto, O. (2000) Role of
the carbonate radical anion in tyrosine nitration and hydroxyla-
tion by peroxynitrite. Arch. Biochem. Biophys. 377, 146-152.
(27) Lakshmi, V. M., Hsu, F. F., Davis, B. B., and Zenser, T. V. (2000)
Nitrating reactive nitric oxygen species transform acetaminophen
to 3-nitro-acetaminophen. Chem. Res. Toxicol. 13, 891-899.
(28) Malejka-Giganti, D., and Ritter, C. L. (1994) Peroxidative me-
tabolism of carcinogenic N-arylhydroxamic acids: implications for
tumorigenesis. Environ. Health Perspect. 102 (Suppl. 6), 75-81.
(29) Culp, S. J ., Roberts, D. W., Talaska, G., Lang, N. P., Ru, P. P.,
Lay, J . O., J r., Teitel, C. H., Snawder, J . E., Von Tungeln, L. S.,
and Kadlubar, F. F. (1997) Immunochemical, 32P-postlabeling, and
GC/MS detection of 4-aminobiphenyl-DNA adducts in human
peripheral lung in relation to metabolic activation pathways
involving pulmonary N-oxidation, conjugation, and peroxidation.
Mutat. Res. 378, 97-112.
(30) Marquez, L. A., and Dunford, H. B. (1997) Mechanism of oxidation
of 3,5,3′,5′-tetramethylbenzidine by myeloperoxidase determined
by transient- and steady-state kinetics. Biochemistry 36, 9349-
9355.
(31) Lakshmi, V. M., Hsu, F. F., Davis, B. B., and Zenser, T. V. (2000)
N-Acetylbenzidine-DNA adduct formation by phorbol 12-myristate
stimulated human polymorphonuclear neutrophils. Chem. Res.
Toxicol. 13, 785-792.
(32) Karreth, S., and Lenk, W. (1991) The metabolism of 4-aminobi-
phenyl in rat. III. Urinary metabolites of 4-aminobiphenyl.
Xenobiotica 21, 709-724.
(33) Green, L. C., Wagner, D. A., Glogowski, J ., Skipper, P. L.,
Wishnok, J . S., and Tannenbaum, S. R. (1982) Analysis of nitrate,
nitrite, and [15N]nitrate in biological fluids. Anal. Biochem. 126,
131-138.
(34) Zwirner-Baier, I., and Neumann, H.-G. (1998) Biomonitoring of
aromatic amines V: acetylation and deacetylation in the meta-
bolic activation of aromatic amines as determined by haemoglobin
binding. Arch. Toxicol. 72, 499-504.
(35) Birner, G., Albrecht, W., and Neuman, H.-G. (1990) Biomonitoring
of aromatic amines III: Hemoglobin binding of benzidine and
some benzidine congeners. Arch. Toxicol. 64, 97-102.
(36) Radomski, J . L. (1979) The primary aromatic amines: Their
biological properties and structure-activity relationships. Annu.
Rev. Pharmacol. Toxicol. 19, 129-157.
(4) El-Sebai, I. (1981) Carcinoma of urinary bladder in Egypt: current
clinical experience. In Detection of Bladder Cancer Associated with
Schistosomiasis (El-Bolkainy, M. N., and Chu, E. W., Eds.) pp
9-18, The National Cancer Institute, Cairo University and Al-
Ahram Press, Cairo.
(5) Rehn, L. (1895) Blasengeschwulste bei fuchsinarbeitern. Arch.
Klin. Chir. 50, 588-600.
(6) Case, R. A. M., Hosker, M. W., McDonald, D. B., and Pearson, J .
T. (1954) Tumors of the urinary bladder in workmen engaged in
the manufacture and use of certain dyestuff intermediates in the
British chemical industry. Br. J . Ind. Med. 11, 75-104.
(7) Doll, R., and Peto, R. (1981) The Causes of Cancer, Oxford
University Press, New York.
(8) Bi, W., Hayes, R. B., Feng, P., Qi, Y., You, X., Zhen, J ., Zhang,
M., Qu, B., Fu, Z., Chen, M., Chien, H. T. C., and Blot, W. J . (1992)
Mortality and incidence of bladder cancer in benzidine-exposed
workers in China. Am. J . Ind. Med. 21, 481-489.
(9) Bedwani, R. (1998) Schistosomiasis and the risk of bladder cancer.
Br. J . Cancer 7, 1186-1189.
(10) Moncada, S., and Higgs, A. (1993) The L-arginine-nitric oxide
pathway. N. Engl. J . Med. 329, 2002-2012.
(11) Kettle, A. J ., and Winterbourn, C. C. (1997) Myeloperoxidase: a
key regulator of neutrophil oxidant production. Redox Rep. 3,
3-15.
(12) Wink, D. A., Kasprzak, K. S., Maragos, C. M., Elespuru, R. K.,
Misra, M., Dunams, T. M., Cebula, T. A., Koch, W. H., Andrews,
A. W., Allen, J . S., and Keefer, L. K. (1991) DNA deaminating
ability and genotoxicity of nitric oxide and its progenitors. Science
254, 1001-1003.
(13) Mirvish, S. S. (1995) Role of N-nitroso compounds (NOC) and
N-nitrosation in etiology of gastric, esophageal, nasopharyneal
and bladder cancer and contribution to cancer of known exposures
to NOC. Cancer Lett. 93, 17-48.
(14) Wiseman, H., and Halliwell, B. (1996) Damage to DNA by reactive
oxygen and nitrogen species: role in inflammatory disease and
progression to cancer. Biochem. J . 313, 17-29.
(15) Christen, S., Hagen, T. M., Shigenaga, M. K., and Ames, B. N.
(1999) Chronic inflammation, mutation, and cancer. In Microbes
and Malignancy. Infection as a Cause of Human Cancers (Par-
sonnet, J ., Ed.) pp 35-88, Oxford University Press, New York.
(16) Hsu, F.-F., Lakshmi, V., Rothman, N., Bhatnager, V. K., Hayes,
R. B., Kashyap, R., Parikh, D. J ., Kashyap, S. K., Turk, J ., Zenser,
T., and Davis, B. (1996) Determination of benzidine, N-acetyl-
benzidine and N,N′-diacetylbenzidine in human urine by capillary
gas chromatography/negative ion chemical ionization mass spec-
trometry. Anal. Biochem. 234, 183-189.
(37) Grisham, M. B., J ourd’Heuil, D., and Wink, D. A. (1999) Nitric
oxide. I. Physiological chemistry of nitric oxide and its metabo-
lites: implications in inflammation. Am. J . Physiol. 39, G315-G321.
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