Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.
The effects of green tea extract (GTE) on the fetal development and external, visceral and skeletal abnormalities induced by cyclophosphamide were investigated in rats. Pregnant rats were daily administered GTE (100mg/kg) by gavage for 7 d, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11mg/kg) 1h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 94.6%, 41.5% and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation) and skeletal (acrania, vertebral/costal malformations and delayed ossification) abnormalities. When pre-treated with GTE, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with GTE greatly increased mRNA expression and activity of hepatic cytochrome P-450 (CYP) 2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard, while reducing CYP3A expression (a detoxifying enzyme). The results suggest that repeated intake of GTE may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by modulating CYP2B and CYP3A.
Park
Dongsun
D
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, 410 Seongbongro (Gaeshin-dong), Cheongju, Chungbuk 361-763, Republic of Korea.
Jeon
Jeong Hee
JH
Shin
Sunhee
S
Joo
Seong Soo
SS
Kang
Dae-Hyuck
DH
Moon
Seol-Hee
SH
Jang
Min-Jung
MJ
Cho
Yeoung Mi
YM
Kim
Jae Wook
JW
Ji
Hyeong-Jin
HJ
Ahn
Byeongwoo
B
Oh
Ki-Wan
KW
Kim
Yun-Bae
YB
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D028241:Camellia sinensis / Q000737:chemistry*; D003520:Cyclophosphamide / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010936:Plant Extracts / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013662:Tea; D013723:Teratogens / Q000633:toxicity*
D010936:Plant Extracts; D012333:RNA, Messenger; D013662:Tea; D013723:Teratogens; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A