Kleiner Heather E, Vulimiri Suryanarayana V, Starost Matthew F, Reed Melissa J, DiGiovanni John
University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Department of Carcinogenesis, PO Box 389, Smithville, TX 78957, USA.
Carcinogenesis. 2002 Oct;23(10):1667-75. doi: 10.1093/carcin/23.10.1667.
The current study was designed to evaluate the effects of oral administration of the citrus coumarin, isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with isopimpinellin and imperatorin. Mice were treated orally with corn oil, isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
本研究旨在评估口服柑橘香豆素异茴芹素对局部应用苯并[a]芘（B[a]P）和7,12-二甲基苯并[a]蒽（DMBA）引发皮肤肿瘤的影响。为评估口服异茴芹素对B[a]P和DMBA引发皮肤肿瘤的影响，首先评估了其对DNA加合物形成的影响。雌性SENCAR小鼠在局部应用B[a]P或DMBA前24小时和2小时，分别用玉米油或异茴芹素（70毫克/千克体重，口服）预处理两次。另一种柑橘香豆素欧前胡素也包含在这些实验中用于比较。口服异茴芹素和欧前胡素分别显著抑制B[a]P-DNA加合物形成37%和26%。欧前胡素还使DMBA-DNA加合物形成减少43%。在第二项剂量反应研究中，口服异茴芹素（35、70和150毫克/千克）分别使DMBA-DNA加合物形成减少23%、56%和69%。对于肿瘤研究，小鼠在DMBA引发前24小时和2小时口服玉米油或异茴芹素进行预处理，2周后用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）开始促进阶段。与玉米油对照组相比，异茴芹素在30、70和150毫克/千克体重时，分别使每只小鼠的乳头状瘤平均数量显著减少49%、73%和78%。口服异茴芹素在最高测试剂量（150毫克/千克）时也显著降低了有乳头状瘤小鼠的百分比。为作比较，还评估了局部应用不同剂量异茴芹素对DMBA引发肿瘤的有效性。作为本研究的一部分，在口服异茴芹素和欧前胡素后评估了几个全身毒性参数。小鼠连续四天每天口服玉米油、异茴芹素或欧前胡素（3
