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

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 (Ahb/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.