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.