Cytochrome P450 3A expression in the human fetal liver: evidence that CYP3A5 is expressed in only a limited number of fetal livers.
CYP3A is the major cytochrome P450 subfamily constitutively expressed in the human liver. CYP3A4 is the predominant hepatic P450 form in adults and it is expressed at high but very variable levels among individuals. The fetal liver contains mainly CYP3A7, while the presence of the other CYP3A enzymes in fetal liver has remained controversial. In this study, the relative levels of CYP3A4, CYP3A5 and CYP3A7 expression were determined in a panel of 9-11 fetal livers with a similar gestation age (9-12 weeks) and compared to adult livers. CYP3A7 was found to be the major CYP3A form in all the fetal liver samples. The abundance of CYP3A7 varied more at the mRNA (77-fold variation) than at the protein level (4.8-fold variation). CYP3A5 mRNA was also detected in all of the fetal liver samples, but the average level was 700-fold lower than that of CYP3A7. CYP3A5 protein was detected by immunoblot analysis in only 1 fetal liver out of the 9 investigated, the level of expression being moderately high in this sample. CYP3A4 mRNA was detected in only a subset of the fetal liver samples and its level was the lowest of the CYP3A forms. This is the first study to demonstrate the polymorphic expression of CYP3A5 and the variability of CYP3A7 expression in fetal liver and suggests that significant interindividual differences in the metabolism of xenobiotics may already exist at the prenatal stage. These differences may contribute to individual pharmacological and/or toxicological responses in the fetus.
Hakkola
J
J
Department of Pharmacology and Toxicology, University of Oulu, Finland. jukka.hakkola@oulu.fi
Raunio
H
H
Purkunen
R
R
Saarikoski
S
S
Vähäkangas
K
K
Pelkonen
O
O
Edwards
R J
RJ
Boobis
A R
AR
Pasanen
M
M
D001189:Aryl Hydrocarbon Hydroxylases; D003001:Cloning, Molecular; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000235:genetics*; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D008099:Liver / Q000196:embryology* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating