Bone marrow toxicity induced by oral benzo[a]pyrene: Protection resides at the level of the intestine and liver

  • Legraverend C
  • Harrison D
  • Ruscetti F
 et al. 
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Abstract

The Ah locus encodes a cytosolic receptor that regulates the induction of certain drug-metabolizing enzymes by polycyclic aromatic hydrocarbons such as benzo[a]pyrene. Some inbred mouse strains such as C57BL 6N have the high-affinity Ah receptor ( AhbAhb), others such as DBA 2N, the poor-affinity receptor ( AhdAhd). Presence of the high-affinity receptor leads to greater cytochrome P1-450 induction by benzo[a]pyrene; in turn, enhanced benzo[a]pyrene metabolism can result in more toxic intermediates or greater detoxication, depending upon the test system studied. Benzo[a]pyrene in the growth medium, in direct contact with cultured myeloid cells, is more toxic to C57BL 6N than DBA 2N cultured cells. Oral benzo[a]pyrene induces P1-450 (measured by benzo[a]pyrene trans-7,8-dihydrodiol formation determined by high-performance liquid chromatography) in C57BL 6N but not DBA 2N intestine and liver. In the bone marrow of oral benzo[a]pyrene-treated C57BL 6N and DBA 2N mice, the magnitude of P1-450 induction is about the same. WB ReJ ( AhdAhd), C57BL 6J ( AhbAhb), or ( WB ReJ)( C57BL 6J)F1( AhdAhd) marrow was transplanted into lethally irradiated ( WB ReJ)( C57BL 6J)F1mice. DBA 2J ( AhdAhd) marrow was transplanted into lethally irradiated BALB cByJ ( AhbAhb) mice and vice versa. Mice having the AhdAhdintestine and liver died in less than 3 weeks of benzo[a]pyrene feeding (120 mg/kg/day), irrespective of the source of transfused marrow. All the data are consistent with pharmacokinetic differences in the tissue distribution of benzo[a]pyrene: mice having the high-affinity receptor, and therefore the P1-450 induction process in the intestine and liver, are protected from oral benzo[a]pyrene-induced myelotoxicity. © 1983.

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Authors

  • Catherine Legraverend

  • David E. Harrison

  • Francis W. Ruscetti

  • Daniel W. Nebert

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