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 ( Ahb Ahb), others such as DBA 2N, the poor-affinity receptor ( Ahd Ahd). 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 ( Ahd Ahd), C57BL 6J ( Ahb Ahb), or ( WB ReJ)( C57BL 6J)F1 ( Ahd Ahd) marrow was transplanted into lethally irradiated ( WB ReJ)( C57BL 6J)F1 mice. DBA 2J ( Ahd Ahd) marrow was transplanted into lethally irradiated BALB cByJ ( Ahb Ahb) mice and vice versa. Mice having the Ahd Ahd intestine 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.
Legraverend, C., Harrison, D. E., Ruscetti, F. W., & Nebert, D. W. (1983). Bone marrow toxicity induced by oral benzo[a]pyrene: Protection resides at the level of the intestine and liver. Toxicology and Applied Pharmacology, 70(3), 390–401. https://doi.org/10.1016/0041-008X(83)90157-6