Uno Shigeyuki, Dalton Timothy P, Dragin Nadine, Curran Christine P, Derkenne Sandrine, Miller Marian L, Shertzer Howard G, Gonzalez Frank J, Nebert Daniel W
Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
Mol Pharmacol. 2006 Apr;69(4):1103-14. doi: 10.1124/mol.105.021501. Epub 2005 Dec 23.
CYP1A1 and CYP1B1 metabolically activate many polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene, to reactive intermediates associated with toxicity, mutagenesis, and carcinogenesis. Paradoxically, however, Cyp1a1-/- knockout mice are more sensitive to oral benzo[a]pyrene exposure, compared with wild-type Cyp1a1+/+ mice (Mol Pharmacol 65:1225, 2004). To further investigate the mechanism for this enhanced sensitivity, Cyp1a1-/-, Cyp1a2-/-, and Cyp1b1-/- single-knockout, Cyp1a1/1b1-/- and Cyp1a2/1b1-/- double-knockout, and Cyp1+/+ wild-type mice were analyzed. After administration of oral benzo[a]pyrene (125 mg/kg/day) for 18 days, Cyp1a1-/- mice showed marked wasting, immunosuppression, and bone marrow hypocellularity, whereas the other five genotypes did not. After 5 days of feeding, steady-state blood levels of benzo[a]pyrene were approximately 25 and approximately 75 times higher in Cyp1a1-/- and Cyp1a1/1b1-/- mice, respectively, than in wild-type mice. Benzo[a]pyrene-DNA adduct levels were highest in liver, spleen, and marrow of Cyp1a1-/- and Cyp1a1/1b1-/- mice. Many lines of convergent data obtained with oral benzo[a]pyrene dosing suggest that: 1) inducible CYP1A1, probably in both intestine and liver, is most important in detoxication; 2) CYP1B1 in spleen and marrow is responsible for metabolic activation of benzo[a]pyrene, which results in immune damage in the absence of CYP1A1; 3) both thymus atrophy and hepatocyte hypertrophy are independent of CYP1B1 metabolism but rather may reflect long-term activation of the aryl hydrocarbon receptor; and 4) the magnitude of immune damage in Cyp1a1-/- and Cyp1a1/1b1-/- mice is independent of plasma benzo[a]pyrene and total-body burden and clearance. Thus, a balance between tissue-specific expression of the CYP1A1 and CYP1B1 enzymes governs sensitivity of benzo[a]pyrene toxicity and, possibly, carcinogenicity.
细胞色素P450 1A1（CYP1A1）和细胞色素P450 1B1（CYP1B1）可将包括苯并[a]芘在内的多种多环芳烃代谢活化为与毒性、诱变和致癌作用相关的反应性中间体。然而，矛盾的是，与野生型Cyp1a1+/+小鼠相比，Cyp1a1-/-基因敲除小鼠经口接触苯并[a]芘时更为敏感（《分子药理学》65:1225，2004年）。为了进一步研究这种增强的敏感性机制，对Cyp1a1-/-、Cyp1a2-/-和Cyp1b1-/-单基因敲除小鼠、Cyp1a1/1b1-/-和Cyp1a2/1b1-/-双基因敲除小鼠以及Cyp1+/+野生型小鼠进行了分析。经口给予苯并[a]芘（125 mg/kg/天）18天后，Cyp1a1-/-小鼠出现明显消瘦、免疫抑制和骨髓细胞减少，而其他五种基因型小鼠未出现上述情况。喂食5天后，Cyp1a1-/-和Cyp1a1/1b1-/-小鼠体内苯并[a]芘的稳态血药浓度分别比野生型小鼠高约25倍和约75倍。苯并[a]芘-DNA加合物水平在Cyp1a1-/-和Cyp1a1/1b1-/-小鼠的肝脏、脾脏和骨髓中最高。通过经口给予苯并[a]芘所获得的多条趋同数据表明：1）诱导型CYP1A1可能在肠道和肝脏中均发挥作用，在解毒过程中最为重要；2）脾脏和骨髓中的CYP1B1负责苯并[a]芘的代谢活化，在缺乏CYP1A1时会导致免疫损伤；3）胸腺萎缩和肝细胞肥大均与CYP1B1代谢无关，而可能反映芳烃受体的长期激活；4）Cyp1a1-/-和Cyp1a1/1b1-/-小鼠的免疫损伤程度与血浆苯并[a]芘水平、全身负荷及清除率无关。因此，CYP1A1和CYP1B1酶的组织特异性表达之间的平衡决定了苯并[a]芘毒性以及可能的致癌性的敏感性。
