DELAYED ONTOGENY OF CYP1A2 IN THE HUMAN LIVER

The ontogenesis of CYP1A proteins was investigated in a human liver ba nk composed of fetal, neonatal and adult samples. In immunoblots, a po lyclonal antibody raised against rat CYP1A1, crossreacted with cDNA-ex pressed human CYP1A1 and CYP1A2. In adult liver microsomes, this antib ody 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 in fants aged 1-3 months to attain 50% of the adult value at one year. En zymatic activities supported by CYP1A proteins were assayed on these s amples. Methoxyresorufin demethylase supported by the CYP1A2 recombina nt protein followed the same ontogenic profile as the CYP1A2 protein. In liver microsomes, the demethylation of imipramine was essentially d ue to CYP1A2 and to a smaller extent to CYP3A. In fetuses and early ne onates, CYP3A proteins were responsible for the low demethylation of i mipramine (3-4% of the adult activity) before the onset of CYP1A2 and the subsequent rise of activity. Immunodetection and enzymatic activit ies were consistent with the absence of CYP1A1 and the late expression of CYP1A2 in the human liver, compared to the early rise of CYP3A4, C YP2C, CYP2D6, and CYP2E1 proteins.