Delayed ontogenesis of CYP1A2 in the human liver.
The ontogenesis of CYP1A proteins was investigated in a human liver bank composed of fetal, neonatal and adult samples. In immunoblots, a polyclonal antibody raised against rat CYP1A1, cross-reacted with cDNA-expressed human CYP1A1 and CYP1A2. In adult liver microsomes, this antibody reacted with a single band identified as the CYP1A2 protein, while no CYP1A1 could be detected. CYP1A2 protein was absent in microsomes prepared from fetal and neonatal livers and its levels increased in infants aged 1-3 months to attain 50% of the adult value at one year. Enzymatic activities supported by CYP1A proteins were assayed on these samples. Methoxyresorufin demethylase supported by the CYP1A2 recombinant protein followed the same ontogenic profile as the CYP1A2 protein. In liver microsomes, the demethylation of imipramine was essentially due to CYP1A2 and to a smaller extent to CYP3A. In fetuses and early neonates, CYP3A proteins were responsible for the low demethylation of imipramine (3-4% of the adult activity) before the onset of CYP1A2 and the subsequent rise of activity. Immunodetection and enzymatic activities were consistent with the absence of CYP1A1 and the late expression of CYP1A2 in the human liver, compared to the early rise of CYP3A4, CYP2C, CYP2D6, and CYP2E1 proteins.
Sonnier
M
M
INSERM U75, Université René Descartes, Paris, France.
Cresteil
T
T
D000328:Adult; D000375:Aging / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000196:embryology / Q000254:growth & development*; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D013379:Substrate Specificity; D014162:Transfection
D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2