Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus

Daniel W. Nebert, Roy C. Levitt, Nancy M. Jensen, George H. Lambert, James S. Felton

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The balance between cytochrome(s) P1-450 and other forms of P-450 in the liver, and probably many nonhepatic tissues as well, appears to be important in the toxicity, carcinogenicity, mutagenicity, and teratogenicity of numerous compounds. Thus, allelic differences in a single gene - the Ah locus -can have profound effects on the susceptibility of mice to drug toxicity and cancer. There is evidence for the Ah locus in the human. Striking increases in the incidence of stillborns, resorptions, and malformations caused by 3-methylcholanthrene or 7,12-dimethylbenz[a]anthracene were observed in the aromatic hydrocarbon "responsive" C57BL/6N, C3H/HeN, and BALB/cAnN inbred strains, compared with the genetically "nonresponsive" AKR/N. These data suggest that an association exists between the Ah locus and teratogenesis. Although numerous teratogenic differences among inbred mouse strains have been previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance, on the basis of known differences in polycyclic hydrocarbon metabolism regulated by the Ah locus. Aplastic anemia induced by oral benzo[a]pyrene daily occurs in less than 4 weeks in the nonresponsive Ahd/Ahd individual, whereas his responsive Ahb/Ahb and Ahb/Ahd siblings remain healthy for 6 months while continuously receiving the same daily dose of benzo[a]pyrene. This phenomenon is probably associated with the "first-pass elimination" effect and the relatively high degree of aryl hydrocarbon hydroxylase induction in the bowel, liver, and bone marrow of the Ahb/Ahb or Ahb/Ahd mouse. A latency period of 2-4 weeks is demonstrated between the exposure of Ahd/Ahd mice to oral benzo[a]pyrene and death; morphological changes of toxicity are apparent early during this latency period. We propose that this animal model system might be useful in investigating human genetic differences in susceptibility to drug-induced aplastic anemia.

Original languageEnglish (US)
Pages (from-to)109-132
Number of pages24
JournalArchives of Toxicology
Volume39
Issue number1-2
DOIs
StatePublished - Mar 1 1977

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Keywords

  • Aplastic anemia
  • Benzo[a]pyrene
  • Bone marrow toxicity
  • Cytochrome P-450
  • Drugmetabolizing enzyme induction
  • Inbred mouse strain
  • Monooxygenase
  • Pharmacogenetics
  • Teratology/teratogenicity/birth defects

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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