Legraverend C, Harrison D E, Ruscetti F W, Nebert D W
Toxicol Appl Pharmacol. 1983 Sep 30;70(3):390-401. doi: 10.1016/0041-008x(83)90157-6.
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.
Ah基因座编码一种胞质受体，该受体可调节多环芳烃（如苯并[a]芘）对某些药物代谢酶的诱导作用。一些近交系小鼠品系，如C57BL/6N，具有高亲和力的Ah受体（Ahb/Ahb），而其他品系，如DBA/2N，则具有低亲和力受体（Ahd/Ahd）。高亲和力受体的存在会导致苯并[a]芘对细胞色素P1-450的诱导作用增强；反过来，根据所研究的测试系统，苯并[a]芘代谢的增强可能会产生更多的毒性中间体或更大程度的解毒作用。生长培养基中与培养的髓细胞直接接触的苯并[a]芘，对C57BL/6N培养细胞的毒性比对DBA/2N培养细胞的毒性更大。口服苯并[a]芘可在C57BL/6N小鼠的肠道和肝脏中诱导P1-450（通过高效液相色谱法测定苯并[a]芘反式-7,8-二氢二醇的形成来衡量），但在DBA/2N小鼠中则不会。在口服苯并[a]芘处理的C57BL/6N和DBA/2N小鼠的骨髓中，P1-450的诱导程度大致相同。将WB/ReJ（Ahd/Ahd）、C57BL/6J（Ahb/Ahb）或（WB/ReJ）（C57BL/6J）F1（Ahb/Ahd）骨髓移植到经致死剂量照射的（WB/ReJ）（C57BL/6J）F1小鼠体内。将DBA/2J（Ahd/Ahd）骨髓移植到经致死剂量照射的BALB/cByJ（Ahb/Ahb）小鼠体内，反之亦然。无论输注骨髓的来源如何，具有Ahd/Ahd肠道和肝脏的小鼠在喂食苯并[a]芘（120 mg/kg/天）不到3周内死亡。所有数据均与苯并[a]芘组织分布的药代动力学差异一致：具有高亲和力受体的小鼠，因此在肠道和肝脏中具有P1-450诱导过程，可免受口服苯并[a]芘诱导的骨髓毒性。
