D. Lacroix et al., EXPRESSION OF CYP3A IN THE HUMAN LIVER - EVIDENCE THAT THE SHIFT BETWEEN CYP3A7 AND CYP3A4 OCCURS IMMEDIATELY AFTER BIRTH, European journal of biochemistry, 247(2), 1997, pp. 625-634
CYP3A isoforms are responsible for the biotransformation of a wide var
iety of exogenous chemicals and endogenous steroids in human tissues.
Two members of the CYP3A subfamily display developmentally regulated e
xpression in the liver; CYP3A7 is expressed in the fetal liver, wherea
s CYP3A4 is the major cytochrome P-450 isoform present in the adult li
ver. To gain insight into the descriptive ontogenesis of CYP3A isoform
s during the neonatal period, we have developed several approaches to
explore a neonatal liver bank. Although CYP3A4 and CYP3A7 are structur
ally closely related, they differ in their capacity to carry out monoo
xygenase reactions. We have cloned CYP3A4 and CYP3A7 and established s
table transfectants in Ad293 cells to investigate their substrate spec
ificities. The 16 alpha hydroxylation of dehydroepiandrosterone is cat
alyzed by both proteins: but CYP3A7 has a higher affinity and maximal
velocity than CYP3A4. Conversely, the conversion of testosterone into
its 6 beta derivative is essentially supported by CYP3A4. We used thes
e two probes to determine the ontogenic evolution at the protein level
; CYP3A7 was very active in the fetal liver and its activity was maxim
al during the first week following birth before to progressively decli
ne and reached a very low level in adult livers. Conversely, the activ
ity of CYP3A4 was extremely weak in the fetus and began to raise after
birth to reach 30-40% of the adult activity after one month. CYP3A4 R
NA accumulation displays a similar pattern of evolution; when probed w
ith an oligonucleotide, its concentration increased rapidly after birt
h to reach a plateau as soon as the first week of age. These data supp
orts the assumption that CYP3A4 expression is transcriptionally activa
ted during the first week after birth and is accompanied by a simultan
eous decrease of CYP3A7 expression, in such a way that the overall CYP
3A protein content and the level of pentoxyresorufin dealkylase cataly
zed by the two proteins remain nearly constant.