Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1981 Jun;39:11–22. doi: 10.1289/ehp.813911

Genetic differences in susceptibility to chemically induced myelotoxicity and leukemia.

D W Nebert
PMCID: PMC1568727  PMID: 7016519

Abstract

The Ah locus represents a complex "cluster" of genese controlling the induction of numerous drug-metabolizing enzyme "activities" by polycyclic aromatic compounds. Allelic differences at the Ah locus are reflected in the large differences in inducibility of cytochrome P1-450 and benzo[a]pyrene metabolism in numerous tissues when the mice receive the chemical daily in their diet. This experimental model system offers to the hematologist and clinical pharmacologist a means to study genetic differences in toxic chemical depression of the bone marrow, as well as a potential model to study aplastic anemia and leukemia explainable on a single-gene basis. The genetically "responsive" individual who is at increased risk for cancer caused by subcutaneous or topical or intratracheal polycyclic hydrocarbons is at decreased risk for toxicity of the bone marrow and leukemia caused by oral benzo[a]pyrene (when compared with the genetically "nonresponsive" individual receiving the same dose of the same xenobiotic). In other words, tissue sites in direct contact with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dose but the route of administration and the tissue in which the malignancy or toxicity develops are therefore very important in the interpretation of data from tumorigenesis or toxicity experiments involving P1-450 inducers such as polycyclic hydrocarbons. There exists sufficient evidence that heritable variation of the Ah locus occurs in man. Growing evidence indicates that persons with higher aryl hydrocarbon hydroxylase inducibility in their cultured mitogen-activated lymphocytes may have a statistically significantly increased risk for certain types of cancer and drug toxicity. It remains to be determined at the present time, however, whether this genotype can be used as a biochemical marker in the individual patient for predicting increased susceptibility to certain types of environmentally caused cancers or toxicity in man.

Full text

PDF
11

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atlas S. A., Nebert D. W. Pharmacogenetics: a possible pragmatic perspective in neoplasm predictability. Semin Oncol. 1978 Mar;5(1):89–106. [PubMed] [Google Scholar]
  2. Benedict W. F., Considine N., Nebert D. W. Genetic differences in aryl hydrocarbon hydroxylase induction and benzo(a)pyrene-produced tumorigenesis in the mouse. Mol Pharmacol. 1973 Mar;9(2):266–277. [PubMed] [Google Scholar]
  3. Chattopadhyay S. K., Lowy D. R., Teich N. M., Levine A. S., Rowe W. P. Qualitative and quantitative studies of AKR-type murine leukemia virus sequences in mouse DNA. Cold Spring Harb Symp Quant Biol. 1975;39(Pt 2):1085–1101. doi: 10.1101/sqb.1974.039.01.124. [DOI] [PubMed] [Google Scholar]
  4. Cohen S. B., Burk R. F. Acetaminophen overdoses at a county hospital: a year's experience. South Med J. 1978 Nov;71(11):1359-63, 1365. doi: 10.1097/00007611-197811000-00013. [DOI] [PubMed] [Google Scholar]
  5. Coomes M. L., Mason W. A., Muijsson I. E., Cantrell E. T., Anderson D. E., Busbee D. L. Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase in cultured human lymphocytes. Biochem Genet. 1976 Aug;14(7-8):671–685. doi: 10.1007/BF00485845. [DOI] [PubMed] [Google Scholar]
  6. Duran-Reynals M. L., Lilly F., Bosch A., Blank K. J. The genetic basis of susceptibility to leukemia induction in mice by 3-methylcholanthrene applied percutaneously. J Exp Med. 1978 Feb 1;147(2):459–469. doi: 10.1084/jem.147.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. ERSLEV A. J., WINTROBE M. M. Detection and prevention of drug-induced blood dyscrasias. JAMA. 1962 Jul 14;181:114–119. doi: 10.1001/jama.1962.03050280044005e. [DOI] [PubMed] [Google Scholar]
  8. Emery A. E., Anand R., Danford N., Duncan W., Paton L. Aryl-hydrocarbon-hydroxylase inducibility in patients with cancer. Lancet. 1978 Mar 4;1(8062):470–472. doi: 10.1016/s0140-6736(78)90135-6. [DOI] [PubMed] [Google Scholar]
  9. Essigmann J. M., Croy R. G., Nadzan A. M., Busby W. F., Jr, Reinhold V. N., Büchi G., Wogan G. N. Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc Natl Acad Sci U S A. 1977 May;74(5):1870–1874. doi: 10.1073/pnas.74.5.1870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gahmberg C. G., Sekki A., Kosunen T. U., Holsti L. R., Mäkelä O. Induction of aryl hydrocarbon hydroxylase activity and pulmonary carcinoma. Int J Cancer. 1979 Mar 15;23(3):302–305. doi: 10.1002/ijc.2910230305. [DOI] [PubMed] [Google Scholar]
  11. Guirgis H. A., Lynch H. T., Mate T., Harris R. E., Wells I., Caha L., Anderson J., Maloney K., Rankin L. Aryl-hydrocarbon hydroxylase activity in lymphocytes from lung cancer patients and normal controls. Oncology. 1976;33(3):105–109. doi: 10.1159/000225116. [DOI] [PubMed] [Google Scholar]
  12. Gurtoo H. L., Minowada J., Paigen B., Parker N. B., Hayner N. T. Factors influencing the measurement and the reproducibility of aryl hydrocarbon hydroxylase activity in culutred human lymphocytes. J Natl Cancer Inst. 1977 Sep;59(3):787–798. doi: 10.1093/jnci/59.3.787. [DOI] [PubMed] [Google Scholar]
  13. Jett J. R., Moses H. L., Branum E. L., Taylor W. F., Fontana R. S. Benzo(a)pyrene metabolism and blast transformation in peripheral blood mononuclear cells from smoking and nonsmoking populations and lung cancer patients. Cancer. 1978 Jan;41(1):192–200. doi: 10.1002/1097-0142(197801)41:1<192::aid-cncr2820410128>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  14. Jones K. G., Sweeney G. D. Dependence of the porphyrogenic effect of 2,3,7,8-tetrachlorodibenzo(p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness. Toxicol Appl Pharmacol. 1980 Mar 30;53(1):42–49. doi: 10.1016/0041-008x(80)90379-8. [DOI] [PubMed] [Google Scholar]
  15. Kellermann G., Shaw C. R., Luyten-Kellerman M. Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N Engl J Med. 1973 Nov 1;289(18):934–937. doi: 10.1056/NEJM197311012891802. [DOI] [PubMed] [Google Scholar]
  16. Kouri R. E., Ratrie H., 3rd, Whitmire C. E. Genetic control of susceptibility to 3-methylcholanthrene-induced subcutaneous sarcomas. Int J Cancer. 1974 May 15;13(5):714–720. doi: 10.1002/ijc.2910130515. [DOI] [PubMed] [Google Scholar]
  17. LUBELL D. L. Fatal hepatic necrosis associated with zoxazolamine therapy. N Y State J Med. 1962 Dec 1;62:3807–3810. [PubMed] [Google Scholar]
  18. Legraverend C., Mansour B., Nebert D. W., Holland J. M. Genetic differences in benzo[a]pyrene-initiated tumorigenesis in mouse skin. Pharmacology. 1980;20(5):242–255. doi: 10.1159/000137370. [DOI] [PubMed] [Google Scholar]
  19. Lieberman J. Aryl hydrocarbon hydroxylase in bronchogenic carcinoma. N Engl J Med. 1978 Mar 23;298(12):686–687. doi: 10.1056/NEJM197803232981213. [DOI] [PubMed] [Google Scholar]
  20. Mattison D. R., Thorgeirsson S. S. Ovarian aryl hydrocarbon hydroxylase activity and primordial oocyte toxicity of polycyclic aromatic hydrocarbons in mice. Cancer Res. 1979 Sep;39(9):3471–3475. [PubMed] [Google Scholar]
  21. McLemore T. L., Martin R. R., Springer R. R., Wray N., Cantrell E. T., Busbee D. L. Aryl hydrocarbon hydroxylase activity in pulmonary alveolar macrophages and lymphocytes from lung cancer and noncancer patients: a correlation with family histories of cancer. Biochem Genet. 1979 Oct;17(9-10):795–806. doi: 10.1007/BF00504304. [DOI] [PubMed] [Google Scholar]
  22. Nebert D. W., Jensen N. M. Benzo[a]pyrene-initiated leukemia in mice. Association with allelic differences at the Ah locus. Biochem Pharmacol. 1979;28(1):149–151. doi: 10.1016/0006-2952(79)90284-3. [DOI] [PubMed] [Google Scholar]
  23. Nebert D. W., Jensen N. M., Levitt R. C., Felton J. S. Toxic chemical depression of the bone marrow and possible aplastic anemia explainable on a genetic basis. Clin Toxicol. 1980 Mar;16(1):99–122. doi: 10.3109/15563658008989927. [DOI] [PubMed] [Google Scholar]
  24. Nebert D. W., Jensen N. M. The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemicals by cytochrome P-450-mediated monooxygenases. CRC Crit Rev Biochem. 1979;6(4):401–437. doi: 10.3109/10409237909105427. [DOI] [PubMed] [Google Scholar]
  25. Nebert D. W., Levitt R. C., Jensen N. M., Lambert G. H., Felton J. S. Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus. Arch Toxicol. 1977 Dec 30;39(1-2):109–132. doi: 10.1007/BF00343280. [DOI] [PubMed] [Google Scholar]
  26. Nebert D. W. Multiple forms of inducible drug-metabolizing enzymes: a reasonable mechanism by which any organism can cope with adversity. Mol Cell Biochem. 1979 Sep 28;27(1):27–46. doi: 10.1007/BF00849277. [DOI] [PubMed] [Google Scholar]
  27. Negishi M., Nebert D. W. Structural gene products of the Ah locus. Genetic and immunochemical evidence for two forms of mouse liver cytochrome P-450 induced by 3-methylcholanthrene. J Biol Chem. 1979 Nov 10;254(21):11015–11023. [PubMed] [Google Scholar]
  28. Okey A. B., Bondy G. P., Mason M. E., Kahl G. F., Eisen H. J., Guenthner T. M., Nebert D. W. Regulatory gene product of the Ah locus. Characterization of the cytosolic inducer-receptor complex and evidence for its nuclear translocation. J Biol Chem. 1979 Nov 25;254(22):11636–11648. [PubMed] [Google Scholar]
  29. Paigen B., Gurtoo H. L., Minowada J., Houten L., Vincent R., Paigen K., Parker N. B., Ward E., Hayner N. T. Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk. N Engl J Med. 1977 Aug 18;297(7):346–350. doi: 10.1056/NEJM197708182970702. [DOI] [PubMed] [Google Scholar]
  30. Paigen B., Ward E., Steenland K., Havens M., Sartori P. Aryl hydrocarbon hydroxylase inducibility is not altered in bladder cancer patients or their progeny. Int J Cancer. 1979 Mar 15;23(3):312–315. doi: 10.1002/ijc.2910230307. [DOI] [PubMed] [Google Scholar]
  31. Paigen B., Ward E., Steenland K., Houten L., Gurtoo H. L., Minowada J. Aryl hydrocarbon hydroxylase in cultured lymphocytes of twins. Am J Hum Genet. 1978 Sep;30(5):561–571. [PMC free article] [PubMed] [Google Scholar]
  32. RUSSELL E. S., BERNSTEIN S. E., MCFARLAND E. C., MODEEN W. R. THE CELLULAR BASIS OF DIFFERENTIAL RADIOSENSITIVITY OF NORMAL AND GENETICALLY ANEMIC MICE. Radiat Res. 1963 Dec;20:677–694. [PubMed] [Google Scholar]
  33. Robinson J. R., Felton J. S., Levitt R. C., Thorgeirsson S. S., Nebert D. W. Relationship between "aromatic hydrocarbon responsiveness" and the survival times in mice treated with various drugs and environmental compounds. Mol Pharmacol. 1975 Nov;11(6):850–865. [PubMed] [Google Scholar]
  34. Robinson J. R., Nebert D. W. Genetic expression of aryl hydrocarbon hydroxylase induction. Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol Pharmacol. 1974 May;10(3):484–493. [PubMed] [Google Scholar]
  35. Routledge P. A., Shand D. G. Presystemic drug elimination. Annu Rev Pharmacol Toxicol. 1979;19:447–468. doi: 10.1146/annurev.pa.19.040179.002311. [DOI] [PubMed] [Google Scholar]
  36. Rüdiger H. W., Heisig V., Hain E. Enhanced benzo(a)pyrene metabolism and formation of DNA adducts in monocytes of patients with lung cancer. J Cancer Res Clin Oncol. 1980;96(3):295–302. doi: 10.1007/BF00408102. [DOI] [PubMed] [Google Scholar]
  37. SANCHEZ MEDAL L., CASTANEDO J. P., GARCIA ROJAS F. INSECTICIDES AND APLASTIC ANEMIA. N Engl J Med. 1963 Dec 19;269:1365–1367. doi: 10.1056/NEJM196312192692508. [DOI] [PubMed] [Google Scholar]
  38. SCHULTZE M. O., KLUBES P., PERMAN V., MIZUNO N. S., BATES F. W., SAUTTER J. H. Blood dyscrasia in calves induced by S-(dichlorovinyl)-L-cysteine. Blood. 1959 Sep;14:1015–1025. [PubMed] [Google Scholar]
  39. Shum S., Jensen N. M., Nebert D. W. The murine Ah locus: in utero toxicity and teratogenesis associated with genetic differences in benzo[a]pyrene metabolism. Teratology. 1979 Dec;20(3):365–376. doi: 10.1002/tera.1420200307. [DOI] [PubMed] [Google Scholar]
  40. Stieglitz R., Stobbe H., Schüttmann W. Knochenmarkschäden nach beruflicher Einwirkung des Insektizids gamma-Hexachlorcyclohexan (Lindan) Acta Haematol. 1967;38(6):337–350. doi: 10.1159/000209035. [DOI] [PubMed] [Google Scholar]
  41. Thomas P. E., Hutton J. J., Taylor B. A. Genetic relationship between aryl hydrocarbon hydroxylase inducibility and chemical carcinogen induced skin ulceration in mice. Genetics. 1973 Aug;74(4):655–659. doi: 10.1093/genetics/74.4.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tokuhata G. K. Smoking in relation to infertility and fetal loss. Arch Environ Health. 1968 Sep;17(3):353–359. doi: 10.1080/00039896.1968.10665241. [DOI] [PubMed] [Google Scholar]
  43. Vessey M. P., Wright N. H., McPherson K., Wiggins P. Fertility after stopping different methods of contraception. Br Med J. 1978 Feb 4;1(6108):265–267. doi: 10.1136/bmj.1.6108.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ward E., Paigen B., Steenland K., Vincent R., Minowada J., Gurtoo H. L., Sartori P., Havens M. B. Aryl hydrocarbon hydroxylase in persons with lung or laryngeal cancer. Int J Cancer. 1978 Oct 15;22(4):384–389. doi: 10.1002/ijc.2910220404. [DOI] [PubMed] [Google Scholar]
  45. Weinstein I. B., Jeffrey A. M., Jennette K. W., Blobstein S. H., Harvey R. G., Harris C., Autrup H., Kasai H., Nakanishi K. Benzo(a)pyrene diol epoxides as intermediates in nucleic acid binding in vitro and in vivo. Science. 1976 Aug 13;193(4253):592–595. doi: 10.1126/science.959820. [DOI] [PubMed] [Google Scholar]
  46. West I. Lindane and hematologic reactions. Arch Environ Health. 1967 Jul;15(1):97–101. doi: 10.1080/00039896.1967.10664883. [DOI] [PubMed] [Google Scholar]
  47. Williams D. M., Lynch R. E., Cartwright G. E. Drug-induced aplastic anemia. Semin Hematol. 1973 Jul;10(3):195–223. [PubMed] [Google Scholar]
  48. Yunis A. A. Chloramphenicol-induced bone marrow suppression. Semin Hematol. 1973 Jul;10(3):225–234. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES