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, on the fetal development and external, visceral, and skeletal abnormalities induced by cyclophosphamide were investigated in rats.


METHODS
Pregnant rats were daily administered PBO (400 mg/kg) by gavage for 7 days (the 6th to 12th day of gestation), and intraperitoneally administered with cyclophosphamide (12 mg/kg) 4 h 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 malformations 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.
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea.
Dongsun
D
Park
Sunghyun
S
Kim
Hyomin
H
Kang
Jiyoung
J
Oh
Ja Young
JY
Jang
Sunhee
S
Shin
Tae Kyun
TK
Kim
Young Jin
YJ
Choi
Sun Hee
SH
Lee
Ki-Yon
KY
Kim
Seong Soo
SS
Joo
Yun-Bae
YB
Kim
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D000284:Administration, Oral; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010574:Pesticide Synergists / Q000494:pharmacology*; D010882:Piperonyl Butoxide / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D004791:Enzyme Inhibitors; D010574:Pesticide Synergists; D012333:RNA, Messenger; D013723:Teratogens; D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1; D010882:Piperonyl Butoxide