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

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 ( Ah b Ah b ), others such as DBA 2N , the poor-affinity receptor ( Ah d Ah d ). Presence of the high-affinity receptor leads to greater cytochrome P 1-450 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 P 1-450 (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 P 1-450 induction is about the same. WB ReJ ( Ah d Ah d ), C57BL 6J ( Ah b Ah b ), or ( WB ReJ )( C57BL 6J ) F 1 ( Ah d Ah d ) marrow was transplanted into lethally irradiated ( WB ReJ )( C57BL 6J ) F 1 mice. DBA 2J ( Ah d Ah d ) marrow was transplanted into lethally irradiated BALB cByJ ( Ah b Ah b ) mice and vice versa. Mice having the Ah d Ah d 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 P 1-450 induction process in the intestine and liver, are protected from oral benzo[ a]pyrene-induced myelotoxicity.