ONSET OF XENOBIOTIC METABOLISM IN CHILDREN - TOXICOLOGICAL IMPLICATIONS

The level of expression of cytochromes P450 shows a wide interindividu al variability, depending on the age and tissue investigated. Several lines of evidence indicate that the human foetal liver is an active si te for the biotransformation of drugs, chemicals and hydrophobic endog enous molecules. Besides this high degree of maturity, many studies ha ve shows a discrepancy in the onset of activities and suggested that c ytochrome P450 isoforms developed independently. Thus, many cytochrome s P450 are absent or barely detectable in the foetal liver and develop postnatally. The postnatal evolution of P450 was explored in a liver bank constituted with samples collected from neonates aged less than 2 4 h to 10 years. Three major groups of cytochrome P450 could be descri bed. a first group of cytrochromes P450 expressed in the foetal liver includes the CYP3A7 and 4A1, mostly active on endogenous substrates; a second group (termed early neonatal P450) includes CYP2D6 and 2E1. Th e surged within hours after birth although proteins could not be detec ted in foetal samples. A third group of P450s (neonatal P450) develops later. CYP3A4 and CYP2Cs rose during the first weeks after parturitio n and CYP1A2 was the last isoform to be expressed in the human liver. Among phase II enzymes, epoxide hydrolase and glutathione S-transferas e pi are very active in the foetal liver, whereas glutathione S-transf erases mu and alpha and UDP-glucuronosyltransferases develop within 3 months after birth. These data clearly emphasize the delayed maturatio n of cel tain biotransformation pathways in the human liver during the perinatal period and constitute a scientific basis for improving safe ty during chemical exposure in children.