Dietary psoralens induce hepatotoxicity in C57 mice.

The psoralens are secondary plant metabolites found in many fruits and vegetables. Synthetic forms of 5-methoxypsoralen (bergapten) and 8-methoxypsoralen (xanthotoxin) have been used in combination with UV radiation in skin photochemotherapy for decades. However, handling or ingestion of psoralen-containing plants as well as medicinal use of these compounds have been shown to cause human health hazards. We evaluated the subacute toxicity of bergapten and xanthotoxin in a mammalian model by mixing individual chemicals into mouse diet at 0, 250, and 1000 ppm, and in combination at 500 ppm each. Feeding on individual dietary treatments at 1000 ppm significantly reduced total liver cytochrome P450 (CYP) levels in female mice compared with the control diet, but not in males. However, combining the two chemicals resulted in a significant induction of total CYP450 in both males and females. Both the combined diet and bergapten at 250 ppm caused a weak induction of CYP1A1. Weight gain was significantly less in males fed either the combined or 1000 ppm diets, while only the combined diet induced a significant weight reduction in females compared with the control diet. The psoralens also caused hypertrophy of centrolobular hepatocytes in livers of treated animals in a manner consistent with morphological alterations seen in rodent livers exposed to liver CYP-inducing agents. Neither bergapten nor xanthotoxin, however, induced a significant dose-dependent toxicity in either male or female mice, suggesting that mice may not represent a good laboratory animal model for evaluating the toxicological effects of psoralens.

Examination of psoralens-induced photodermatitis in Wistar rats under scanning electron microscopy.

The psoralens are photoactivated plant biosynthetic compounds which are found in several plant families, including common fruits and vegetables. Synthetic forms of the psoralens bergapten (5-methoxypsoralen) and xanthotoxin (8-methoxypsoralen) are extensively used in skin chemotherapy in combination with long-wave ultraviolet radiation (PUVA). Side effects of PUVA therapy are not, however, desirable, and this therapy has been linked with increased incidence of skin cancer in humans. The psoralens are known to be carcinogenic, mutagenic and teratogenic, and to cause photodermatitis. The main objective of this study was to document the effect of PUVA on the epidermis of rats. Female Wistar rats were administered dietary bergapten and/or xanthotoxin (0-200 mg/kg body) and exposed to UVA radiation (45 min./day) for four weeks. At the end of the four-week period the rats were sacrificed; skin samples were taken from the ears and the top part of the tail and fixed for examination by Scanning Electron Microscopy. The animals subjected to PUVA had significantly smaller scales on the tail epidermis (mean scale size for the control 926 mu vs. 725 to 805 mu for the psoralen treatment groups. The rats that received dietary psoralens also had significantly less hair on the ears compared with the control animals (mean number of hairs per millimeter over the ear edge for the control 54.9 vs. 2.00 to 10.7 for the treatment groups). The two compounds were synergistic in their ability to reduce scale size on the tail epidermis.

A novel group of ovarian toxicants: the psoralens.

The psoralens are naturally occurring metabolites found in many crop plants; synthetic forms of 5-methoxypsoralen (bergapten) and 8-methoxypsoralen (xanthotoxin) are widely used in skin photochemotherapy. Our previous research documented that dietary bergapten and xanthotoxin reduced birthrates in female rats when males and females were exposed to these chemicals. The present study was designed to determine the cause of this reduced birthrate and whether this resulted from direct impact on the females. The study demonstrates that bergapten and xanthotoxin administered, either alone or in combination to female rats (mated to undosed males), significantly reduced the number of implantation sites, pups, and corpora lutea in dosed females compared with control animals. Additionally, full uterine weight and empty uterine weight were significantly reduced. These compounds also significantly reduced circulating estrogen levels in a dose-dependent manner. Interestingly, the psoralens significantly induced mRNAs of liver enzymes typically induced by polycyclic aromatic hydrocarbons, CYP1A1 and UGT1A6; the higher the dose, the greater the induction. UGT 2B1 mRNA, typically induced by phenobarbital-like compounds, was not significantly affected. Thus, enhanced oxidative metabolism and conjugation of estrogens in psoralen-treated animals may provide a partial explanation for the effects observed. These findings are also consistent with psoralen-induced reduction in ovarian follicular function and ovulation.

Psoralen-induced growth inhibition in Wistar rats.

The linear furanocoumarins (or psoralens) are naturally occurring plant biosynthetic metabolites that have been used since ancient times in skin photochemotherapy. However, medicinal use of the psoralens has been linked with increased incidence of skin cancer in humans. To understand some of the mechanism of this toxicity, we tested increasing concentrations of the psoralens bergapten (5-methoxypsoralen) and xanthotoxin (8-methoxypsoralen) for toxicity against Wistar rats. As dietary concentrations of each compound increased, weight gain in both male and female rats decreased. Feeding on diet containing these chemicals also decreased rat birth rate, but did not significantly affect individual litter weight or date of birth. Xanthotoxin appeared to be more toxic than bergapten.

Toxicity of linear furanocoumarins toSpodoptera exigua: Evidence for antagonistic interactions.

The linear furanocoumarins psoralen, bergapten, and xanthotoxin were tested for toxicity to the beet armywormSpodoptera exigua (Hübner) under short ultraviolet (UVB) radiation. Increased dietary concentrations of each furanocoumarin significantly decreased insect larval weight, extended generation time, and induced higher mortality. Xanthotoxin was the most toxic, followed by psoralen and bergapten. Combining psoralen with bergapten, xanthotoxin, or both resulted in significantly antagonistic effects on insect mortality. The combination of bergapten and xanthotoxin, however, produced additive effects. The implications of these observations forS. exigua resistance in the wild plant accession ofApium prostratum and the enigma the findings represent for plant-insect relationships are discussed.