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.