Onset of xenobiotic metabolism in children: toxicological implications

Abstract

The level of expression of cytochromes P450 shows a wide interindividual variability, depending on the age and tissue investigated. Several lines of evidence indicate that the human foetal liver is an active site for the biotransformation of drugs, chemicals and hydrophobic endogenous molecules. Besides this high degree of maturity, many studies have shown a discrepancy in the onset of activities and suggested that cytochrome P450 isoforms developed independently. Thus, many cytochromes 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 24 h to 10 years. Three major groups of cytochrome P450 could be described: a first group of cytochromes 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. They surged within hours after birth although proteins could not be detected in foetal samples. A third group of P450s (neonatal P450) develops later. CYP3A4 and CYP2Cs rose during the first weeks after parturition and CYP1A2 was the last isoform to be expressed in the human liver. Among phase II enzymes, epoxide hydrolase and glutathione S-transferase pi are very active in the foetal liver, whereas glutathione S-transferases mu and alpha and UDP-glucuronosyltransferases develop within 3 months after birth. These data clearly emphasize the delayed maturation of certain biotransformation pathways in the human liver during the perinatal period and constitute a scientific basis for improving safety during chemical exposure in children.