Defects of pectoral fins caused by thalidomide in human cytochrome P450 3As-expressing zebrafish

抄録

Active metabolites of chemicals by enzymes including cytochrome P450 (CYP) are important in the pharmacological and toxicological effects in some cases. While it has been believed for a long time that thalidomide causes characteristic limb malformation only in rabbits and primates including human, the involvement of their CYP3A subtypes (CYP3As) has been suggested. Recently, it was reported that thalidomide caused defects of zebrafish pectoral fins, homologous organs of limbs in mammals, as well as other deformities. On the other hand, however, it was also reported that conventional aqueous exposure to thalidomide has only little effect in developing zebrafish. In this study, we generated human CYP3A7 (hCYP3A7) -, human CYP3A4 (hCYP3A4)- and human CYP1A1 (hCYP1A1) - expressing zebrafish (F0) using transposon system. Thalidomide caused pectoral fin defects and other malformation including pericardium edema and otic vesicles in both hCYP3A7- and hCYP3A4-expressing zebrafish but not in wild-type and hCYP1A1-expressing embryos/larvae. Thalidomide also reduced expression of fibroblast growth factor 8 in the pectoral fin bud in hCYP3A7-expressing embryos/larvae. The results suggest the involvement of human CYP3As but not by hCYP1A1 in augmentation of thalidomide teratogenicity. hCYPs-expressing zebrafish is an useful model for developmental toxicology.