Establishment of transgenic mice carrying human fetus-specific CYP3A7.
CYP3A7 is a cytochrome P450 isozyme expressed prenatally in humans. Six lines of mice transgenic for human CYP3A7 were established by microinjecting a CYP3A7 cDNA downstream of a mouse metallothionein-1 promoter gene into the male pronucleus of fertilized mouse oocytes. The inserted CYP3A7 transgene was expressed at a mRNA level in a variety of tissues including the liver, kidney, lung, spleen, testis, small intestine, thymus, brain, skin, and heart of adult mice. The protein expression of the transgene was also detected in the liver and testis of line M10 mice. A significantly higher level of total testosterone in the serum was found in line M10 male mice. In addition, this transgenic line exhibited weight increases in the liver, kidney, and uterus but a decrease in the testis (P < 0.01). The transcript of the integrated CYP3A7 gene possessed the ability to activate aflatoxin B1 in Ames test in which the his+ revertants of Salmonella typhimurium TA100 per plate were significantly higher (P < 0.01) when liver microsomes of line M10 transgenic mice were used. This result demonstrates that the CYP3A7 gene has been integrated into the mouse genome and translated into a catalytically active enzyme. These transgenic mice are expected to give useful information for studies on fetal toxicities in humans.
Li
Y
Y
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yokoi
T
T
Kitamura
R
R
Sasaki
M
M
Gunji
M
M
Katsuki
M
M
Kamataki
T
T
D016604:Aflatoxin B1 / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000201:enzymology*; D018628:Gene Dosage; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009153:Mutagens / Q000378:metabolism; D012727:Sex Characteristics; D013045:Species Specificity; D013739:Testosterone / Q000097:blood; D014018:Tissue Distribution; D019076:Transgenes
D007527:Isoenzymes; D009153:Mutagens; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A