Preventive Effect of Piperonyl Butoxide on Cyclophosphamide-Induced Teratogenesis in Rats

BACKGROUND: Cyclophosphamide induces fetal defects through metabolic activation by cytochrome P-450 monooxygenases (CYP). The effects of piperonyl butoxide (PBO), a CYP inhibitor, oil the fetal development and external, visceral, and skeletal abnormalities induced by cyclophosphamide were investigated in rats. METHODS: Pregnant rats were daily administered PBO (400mg/kg) by gavage for 7 days (the 6th to 12th day of gestation), and intraperitoneally administered with cyclophosphamide (12 mg/kg) 4h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarean section RESULTS: Cyclophosphamide reduced fetal body weights by 30-40% without increasing resorption or death In addition, it induced-mal formations in live fetuses: 100, 98 and 98 2% of the external (head and limb defects), visceral (cerebroventricular dilatation, cleft palate, and renal pelvic/ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities respectively. The pre-treatment of PBO greatly decreased mRNA expression and activity of hepatic CYP2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard. Moreover, PBO remarkably attenuated cyclophosphamide-induced body weight loss and abnormalities of fetuses; score 3.57 versus 1 87 for exencephaly, 75.5% versus 42.5% for limb defects, 65.3% versus 22% for cerebroventricular dilatation, 59 2% versus 5.1% for cleft palate, score 1 28 versus 0 93 for renal pelvic/ureteric dilatation, 71.9-82.5% versus 23-45.9% for vertebral/costal malformations, and 84.2% versus 57.4% for delayed ossification in cyclophosphamide alone and PBO co-administration groups. CONCLUSIONS: These results suggest that repeated treatment with PBO may improve cyclophosphamide-induced body weight loss and malformations of fetuses by down-regulating CYP2B Birth Defects Res (Part B) 86:402-408, 2009. (C) 2009 Wiley-Liss, Inc