Developmental Expression of Cytochrome P450 Enzymes in Human Liver

Abstract

Absrruct: Drug-metabolizing cytochrome P450 enzymes, the major phase I enzymes, are active in human liver already at very early stages of intrauterine development, although presumably at f d y low concentrations and in low numben. During maturation. these enzymes go through various developmental programmes towards adulthood. The major increase both in abundance as well as in number of different enzymes takes place after birth, probably during the first year of life. Detailed information concerning these developmental changes is still limited. The major drug-metabolizing P450 enzymes appear to be primarily members of the CYP3A subfamily in all stages of development. The balance between different members of this subfamily, however, undergoes significant switches from the foetal predominant CYP3A7 to the major adult forni CYP3A4. The ontogcny of the other cytochronie P450 enzymes is less well characterized, but the major switchon appears to occur mainly after birth. Developmental expression of P450 enzymes is one of the key factors determining the pharmacokinetic status of developing individuals both pre-and postnatally.

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

“…We note that the positive correlations were mainly driven by low activity levels in very young (<20 yr) subjects. This is consistent with the observation that most P450s turn on after birth and mature over the first years of life (Hakkola et al 1998;Koukouritaki et al 2004). In order to address the relationship between age and P450 activity in adults only (more than 20 yr), we performed additional analyses and found that most of the correlations observed in the all-subject analysis disappeared, suggesting weaker age effect in adults.…”

Neonatal Hepatic Drug Elimination

“…The first observations of oxidative drug metabolism in human foetal liver were made by Yaffe et al (1970) and Pelkonen et al (1971), and although incomplete, a significant amount of data has been obtained over more recent years about foetal and neonatal hepatic P450 isoforms (Treluyer et al 1991(Treluyer et al & 1996Kitada & Kamataki 1994;Hakkola et al 1994;Vieira et al 1996;Hakkola et al 1998). At birth, total neonatal hepatic cytochrome P450 concentration is approximately 30% of adult levels (Treluyer et al 1996(Treluyer et al & 1997.…”

“…Induction by exogenous compounds may be another factor (Denison & Whitlock 1995). This could explain the great variability in expression of various cytochrome P450 isoenzymes in human foetal liver (Treluyer et al 1991;Hakkola et al 1998) and the rapid postnatal surge in cytochrome P450 expression associated with the commencement of oral feeding. Evidence also exists that induction by exogenous compounds may only occur in a pre-programmed ''temporal window'' when the organ is receptive to such stimulation (Atlas et al 1977).…”

Modulation of Pulmonary Cytochrome P4501A1 Expression by Hyperoxia and Inhaled Nitric Oxide in the Newborn Rat: Implications for Lung Injury

“…The CYP enzymes are developmentally regulated (21). Seventy percent of the CYP are constitutively expressed at one stage or another during development of animals and humans and one third of these belong to the CYP1-CYP3 families (21). In rodents, CYP1A1 is detected only at embryonic d 7, CYP1B1 on d 11, 15, and 17, whereas CYP1A2 is not expressed at all during embryonic and fetal development (21).…”

“…P450 enzymes, including CYP1A1, have also been implicated in the formation and further reactions of ROS, and may play a role in pulmonary oxygen toxicity (17)(18)(19)(20). The CYP enzymes are developmentally regulated (21). Seventy percent of the CYP are constitutively expressed at one stage or another during development of animals and humans and one third of these belong to the CYP1-CYP3 families (21).…”