Moorthy B, Sriram P, Randerath K
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Fundam Appl Toxicol. 1994 May;22(4):549-60. doi: 10.1006/faat.1994.1062.
It is well documented that cytochrome P450IA1 (CYP1A1) plays an important role in carcinogen activation. CYP1A1/1A2 induction may serve as a biomarker of exposure to environmental toxins. In order to explore a specific role of CYP1A1 in metabolism of I-compounds (age-dependent indigenous DNA modifications), 2-month-old female Sprague-Dawley rats were treated ip with corn oil (2 ml/kg) or with one of several CYP1A1 inducers, i.e., dibenz[a,c]anthracene (DBA) (93 mumol/kg), benzo[a]pyrene (BP) (93 mumol/kg), naphthacene (NAP) (93 mumol/kg), or beta-naphthoflavone (BNF) (140 mumol/kg), once daily for 4 days. Levels of total cytochrome P450 and activities of CYP1A1-associated enzymes, i.e., ethoxycoumarin O-deethylase (ECD) and ethoxyresorufin O-deethylase (EROD), were determined in liver microsomes at 1, 8, or 15 days after the last treatment. DNA adducts and I-compounds were analyzed by nuclease P1-enhanced 32P-postlabeling. DNA synthesis rate was determined by measuring [3H]methylthymidine incorporation into DNA. Each inducer significantly elevated the total P450 level at 1 day. The enzyme levels in BP-, NAP-, and BNF-treated animals gradually returned to control by 8 and 15 days, but elevated levels persisted in DBA-treated rats. Similar trends were observed for ECD and EROD activities. DBA and BP, but not NAP and BNF, gave rise to several measurable DNA adducts, which persisted throughout the period of study. All P450 inducers, irrespective of adduct formation, strongly depleted both nonpolar and polar I-compounds, the effects being most pronounced at 1 and 8 days. These results imply a specific role for CYP1A1 in the regulation of I-compound metabolism, in addition to PAH activation.
细胞色素P450IA1（CYP1A1）在致癌物激活过程中发挥重要作用，这一点已有充分记录。CYP1A1/1A2的诱导可作为接触环境毒素的生物标志物。为了探究CYP1A1在I-化合物（年龄依赖性内源性DNA修饰）代谢中的特定作用，对2月龄雌性Sprague-Dawley大鼠腹腔注射玉米油（2 ml/kg）或几种CYP1A1诱导剂之一，即二苯并[a,c]蒽（DBA）（93 μmol/kg）、苯并[a]芘（BP）（93 μmol/kg）、并四苯（NAP）（93 μmol/kg）或β-萘黄酮（BNF）（140 μmol/kg），每日一次，共4天。在最后一次处理后的第1、8或15天，测定肝微粒体中总细胞色素P450水平以及CYP1A1相关酶，即乙氧香豆素O-脱乙基酶（ECD）和乙氧试卤灵O-脱乙基酶（EROD）的活性。通过核酸酶P1增强的32P后标记法分析DNA加合物和I-化合物。通过测量[3H]甲基胸苷掺入DNA来测定DNA合成速率。每种诱导剂在第1天均显著提高了总P450水平。BP、NAP和BNF处理组动物的酶水平在第8天和第15天时逐渐恢复至对照水平，但DBA处理组大鼠的酶水平持续升高。ECD和EROD活性也观察到类似趋势。DBA和BP可产生几种可测量的DNA加合物，且在整个研究期间持续存在，而NAP和BNF则不会。所有P450诱导剂，无论是否形成加合物，均强烈消耗非极性和极性I-化合物，在第1天和第8天时效果最为明显。这些结果表明，除了多环芳烃激活外，CYP1A1在I-化合物代谢调节中具有特定作用。
