Moorthy B, Sriram P, Randerath K
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Toxicology. 1995 Dec 15;104(1-3):165-77. doi: 10.1016/0300-483x(95)03181-e.
I-compounds are age-dependent covalent DNA modifications, which occur in rodent tissues without known carcinogen exposure. A number of studies from our laboratory indicate that I-compounds may serve as biomarkers of carcinogenesis. Recently, we demonstrated significant lowering of liver I-compound levels in rats that were exposed to different cytochrome P450 inducers. In order to gain further mechanistic insights into the possible relationship between P450 induction and I-compound reduction, female Sprague-Dawley rats were administered a single dose of the CYP1A1 inducer, beta-naphthoflavone (BNF) (80 mg/kg), in corn oil (CO) (2 ml/kg) or CO only (2 ml/kg) as vehicle control. Liver and kidney microsomal P450 contents and P450-related enzyme activities and DNA I-compounds were determined at 4, 24, and 48 h after treatment. Liver and kidney I-compounds were analyzed by nuclease P1-enhanced 32P-postlabeling. DNA synthesis was determined by measuring [3H]methylthymidine incorporation. Liver and kidney microsomal P450 contents were elevated by BNF at 24 and 48 h. Ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) were significantly elevated at all time points, with the former displaying a much higher extent of induction. BNF treatment resulted in significant diminution of the levels of several individual and total I-compounds in liver at 48 h, but few effects were seen at the earlier time-points. Kidney I-compounds were also markedly affected by BNF at 48 h, albeit to a lesser extent than in liver. In both tissues, P450 induction preceded I-compound reduction. Taken together, the results of this investigation demonstrate significant diminution of I-compound levels by a single dose of BNF, a CYP1A1 inducer, in a time-dependent manner, suggesting the participation of a specific biochemical process, possibly involving CYP1A1, in the metabolic regulation of these endogenous DNA adducts.
I-化合物是一种与年龄相关的共价DNA修饰，它出现在未接触已知致癌物的啮齿动物组织中。我们实验室的多项研究表明，I-化合物可能作为致癌作用的生物标志物。最近，我们证明了暴露于不同细胞色素P450诱导剂的大鼠肝脏中I-化合物水平显著降低。为了进一步深入了解P450诱导与I-化合物减少之间可能的关系，给雌性Sprague-Dawley大鼠单次注射CYP1A1诱导剂β-萘黄酮（BNF）（80mg/kg），溶媒为玉米油（CO）（2ml/kg），或仅注射溶媒玉米油（2ml/kg）作为对照。在处理后4小时、24小时和48小时测定肝脏和肾脏微粒体P450含量、P450相关酶活性以及DNA I-化合物。通过核酸酶P1增强的32P后标记法分析肝脏和肾脏I-化合物。通过测量[3H]甲基胸苷掺入量来测定DNA合成。BNF在24小时和48小时使肝脏和肾脏微粒体P450含量升高。乙氧基异吩恶唑酮-O-脱乙基酶（EROD）和甲氧基异吩恶唑酮-O-脱甲基酶（MROD）在所有时间点均显著升高，前者的诱导程度更高。BNF处理导致48小时时肝脏中几种单个和总I-化合物水平显著降低，但在较早时间点未见明显影响。肾脏I-化合物在48小时时也受到BNF的显著影响，尽管程度小于肝脏。在两种组织中，P450诱导先于I-化合物减少。综上所述，本研究结果表明，单次注射CYP1A1诱导剂BNF可使I-化合物水平以时间依赖性方式显著降低，提示一个特定的生化过程可能参与了这些内源性DNA加合物的代谢调控，该过程可能涉及CYP1A1。
