| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079 [M. A. B., F. F. K.]; and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [F. P. G.]
Metabolic N-oxidation and ring-oxidation of carcinogenic arylamines by hepatic cytochromes P-450 are generally regarded as critical activation and detoxification pathways, respectively. Two arylamines with known human exposure, 4-aminobiphenyl (ABP) and 4,4'-methylene-bis(2-chloroaniline) (MOCA), have been examined as substrates for 10 different purified rat hepatic cytochromes P-450 and for human liver microsomal preparations from 22 individuals. Metabolites were analyzed by high-performance liquid chromatography and flow scintillation techniques. As reported for certain other carcinogenic arylamines, the isosafrole-inducible isozyme, P-450ISF-G, had the highest catalytic activity for ABP N-oxidation (13.6 nmol/min/nmol P-450), but P-450BNF-B, P-450UT-A, P-450UT-F, and P-450PB-B also showed appreciable activity. Ring-oxidation of ABP occurred only to a minor extent. In contrast, N-oxidation of MOCA was preferentially catalyzed by the phenobarbital-inducible enzymes, P-450PB-B and P-450PB-D (9.0 and 6.6 nmol/min/nmol P-450, respectively). MOCA ring-oxidation and methylene carbon oxidation showed varied cytochrome P-450 selectivity and accounted for 14 to 79% of total oxidation products. There was a 44-fold variation in rates of ABP N-oxidation in the 22 human liver microsomal preparations, while rates of N-oxidation of MOCA varied only 8-fold. Ring/methylene carbon-oxidation of MOCA accounted for 6–19% of total oxidation products in the case of the human microsomal preparations, whereas ring-oxidation of ABP accounted for less than 7% of total oxidation. In addition, there was a strong correlation (R = 0.90) between rates of ABP N-oxidation and phenacetin O-deethylation, which is considered a human genetic polymorphism. Moreover, both the ABP N-oxidation and phenacetin O-deethylation activities of human liver microsomes showed a good correlation (R = 0.72) with the levels of cytochrome P-450 immunochemically related to rat P-450ISF-G. These data indicate that specific inducible and constitutive cytochromes P-450 are involved in the metabolic activation and detoxification of the carcinogens ABP and MOCA. Therefore, individual profiles of cytochromes P-450, affected by both environmental and genetic factors, may be significant determinants of individual susceptibility to arylamine carcinogenesis.
1 Supported in part by USPHS Grants ES 00267, ES 01590, and CA 44353.
2 Burroughs Wellcome Scholar in Toxicology (1983–1988).
3 To whom requests for reprints should be addressed, at Division of Biochemical Toxicology, National Center for Toxicological Research, HFT-110, Jefferson, AR 72079.
Received 6/13/88. Revised 9/20/88. Accepted 9/29/88.
This article has been cited by other articles:
|
|
 |
|
  Y. Tsuneoka, T. P. Dalton, M. L. Miller, C. D. Clay, H. G. Shertzer, G. Talaska, M. Medvedovic, and D. W. Nebert 4-Aminobiphenyl-Induced Liver and Urinary Bladder DNA Adduct Formation in Cyp1a2(-/-) and Cyp1a2(+/+) Mice J Natl Cancer Inst, August 20, 2003; 95(16): 1227 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gago-Dominguez, D. A. Bell, M. A. Watson, J.-M. Yuan, J.E. Castelao, D. W. Hein, K. K. Chan, G. A. Coetzee, R. K. Ross, and M. C. Yu Permanent hair dyes and bladder cancer: risk modification by cytochrome P4501A2 and N-acetyltransferases 1 and 2 Carcinogenesis, March 1, 2003; 24(3): 483 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Goldman and P. G. Shields Food Mutagens J. Nutr., March 1, 2003; 133(3): 965S - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Besaratinia, S. E. Bates, and G. P. Pfeifer Mutational Signature of the Proximate Bladder Carcinogen N-Hydroxy-4-acetylaminobiphenyl: Inconsistency with the p53 Mutational Spectrum in Bladder Cancer Cancer Res., August 1, 2002; 62(15): 4331 - 4338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Obach, J. Pablo, and D. C. Mash Cytochrome P4502D6 Catalyzes the O-Demethylation of the Psychoactive Alkaloid Ibogaine to 12-Hydroxyibogamine Drug Metab. Dispos., August 1, 1998; 26(8): 764 - 768. [Abstract] [Full Text]
|
|
|
|
|
|
D. Zalko, E. Perdu-Durand, L. Debrauwer, M.-P. Bec-Ferte, and J. Tulliez Comparative Metabolism of Clenbuterol by Rat and Bovine Liver Microsomes and Slices Drug Metab. Dispos., January 1, 1998; 26(1): 28 - 35. [Abstract] [Full Text]
|
|
|
|
|
|
V. M. Lakshmi, T. V. Zenser, and B. B. Davis Rat Liver Cytochrome P450 Metabolism of N-Acetylbenzidine and N,N'-Diacetylbenzidine Drug Metab. Dispos., April 1, 1997; 25(4): 481 - 488. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y.W. F. Lam and M. V. Marshall Genetically Determined Polymorphisms in Drug Metabolism Journal of Pharmacy Practice, January 1, 1992; 5(6): 317 - 336. [Abstract] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Cell Growth & Differentiation |
