DEVELOPMENTAL EXPRESSION OF CYP2C AND CYP2C-DEPENDENT ACTIVITIES IN THE HUMAN LIVER - IN-VIVO IN-VITRO CORRELATION AND INDUCIBILITY/

Experiments were performed in vivo and in vitro to date the onset of h epatic CYP2C isoforms and CYP2C-dependent activities during the perina tal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespe ctive of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for CYP2C9 was undetected in fetal liver micros omes and rose in the first month after birth. In adult liver preparati ons, the hydroxylation of diazepam correlated well with the CYP3 A con tent of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxyla tion of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In feta l liver microsomes, hydroxylation and demethylation activities account ed for less than 5% of the adult activities and both increased immedia tely after birth to reach adult activities at 1 year of age. When diaz epam was given for sedative purpose in neonates and infants, the in-vi vo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excre ted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acte d as inducers of CYP2C isoforms and increased tolbutamide hydroxylatio n, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occu rring in the first week after birth. The hepatic content in CYP2C8, 2C 9 and 2C18 RNA displayed the same profile of evolution, which suggeste d a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the ons et of CYP2C proteins to the first weeks after birth, which is of consi derable clinical importance in pediatric pharmacology.