Relative importance of maternal and embryonic microsomal epoxide hydrolase in 7,12-dimethylbenz[a]anthracene-induced developmental toxicity.
Microsomal epoxide hydrolase (mEH) catalyzes the hydrolysis of epoxide intermediates derived from drugs and environmental chemicals. The response of in vivo (embryo) and in vitro (embryo fibroblast) tests were analyzed using mEH-null and wild-type mice to determine the relative role of maternal and embryonic mEH in the developmental toxicity induced by 7,12-dimethylbenz[a]anthracene (DMBA). Embryos derived from DMBA-treated [50mg/kg, daily from gestational day (GD) 11 to GD 15] dams were analyzed. Although weight (P=0.0009) and crown-rump length (P=0.0003) of wild-type fetuses on GD 18 were significantly lower than those of mEH-null fetuses, respectively, no significant difference was found between mEH-null and heterozygous fetuses of mEH-null dams. Cell viability was decreased to 50% in wild-type mouse embryo fibroblasts (MEFs) treated with 3 microM DMBA, but no significant decrease was found in mEH-null MEFs. DMBA-3,4-diol produced a significant decrease in cell viability and suppressed the proliferation of wild-type MEFs at a 10-fold lower concentration than did DMBA. Although mEH protein was expressed in liver microsomes from wild-type embryos (GD 15), DMBA-3,4-diol was not detected among the DMBA metabolites. However, it was detected in the serum of wild-type pregnant mice treated with DMBA, but not in that of mEH-null mice. These results suggest that maternal mEH plays a major role in DMBA-induced developmental toxicity, and embryonic mEH is less involved in the toxicity.
Miyata
Masaaki
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. miyata@mail.pharm.tohoku.ac.jp
Motoki
Kazuko
K
Tamura
Etsuko
E
Furukawa
Masayuki
M
Gonzalez
Frank J
FJ
Yamazoe
Yasushi
Y
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; C024024:7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol; D004851:Epoxide Hydrolases