Developmental Differences in CYP2E1 Activity
Age-related
changes in CYP2E1 microsomal content and activity can also be a factor in
individual variability. Several studies
have shown that CYP2E1 protein levels in hepatic microsomes are very low at
birth, but rise rapidly thereafter such that this CYP can become an important metabolizing
component during the first month of life (Treluyer, et al., 1996; Vieira, et
al., 1996 Cresteil, 1998; Johnsrud et al. 2003).
Studies by Vieira et al. (1996) and
Johnsrud et al. (2003) offer the most detailed insight to the developmental changes
in CYP2E1 microsomal content. Vieira et
al. (1996) measured CYP2E1 content in hepatic microsomes from 80 liver samples
and CYP2E1 activity in 70 of those samples as a function of
6-hydroxychloroxazone formation. As discussed earlier, Johnsrud et al., 2003
measured CYP2E1 content in hepatic microsomal protein from 167 donors ranging
in age from birth to 18 years.
The two studies show similar
patterns of CYP2E1 expression with age. Using the geometric means (GM) for the
age groups reported in the original Vieira et al. (1996) paper, Figure 4-1 to
compares the ratio of GM CYP microsomal protein to adult levels for each of the
age groups reported. (The data on which
this figure is based are found in Table 4-2).
Levels are lowest directly after birth but increase rapidly to near
adult levels by early childhood.
Note that the ratios in the first
three age groups in the Vieira et al. (1996) study and the first two age groups
in the Johnsrud et al. (2003) study may
not portray levels typical of full-term newborns. CYP2E1 levels in fetal livers are lower than
those reported here (data not shown).
However, the newborn infants in these age categories were premature (
32-34 weeks gestation in the Vieira et al. 1996 study); the body weights for
the first two age categories in the Johnsrud et al. (2003) study were 1.7 and
2.5 kg indicating that these subjects were also premature. Thus, it is possible that their reported
CYP2E1 levels may be more reflective of 3rd trimester fetal
liver. However, CYP2E1 content of
microsomes is reported to increase rapidly in the days immediately after birth
regardless of gestational age at birth (Vieira, 1996). Thus, this element of the early post natal
data from Johnsrud and Vieira is not likely to create much uncertainty.
Johnsrud et al. (2003) did not find
significant differences in protein expression between the age groupings used by
Vieira et al. (1996) and it is not clear from the Vieira et al. (1996) paper
whether they did either. However, in
order to compare the two studies, we chose to use the Vieira age
groupings. Using DataThief, a data
retrieval program[1],
we estimated the means and standard deviations for each age group from Figure 1
in the Vieira et al. (1996) paper. We
then estimated the GM and GSDs using standard algorithms in Crystal Ball®. We had been provided the Johnsrud et al.
(2003) data, and were able to calculate the same parameters for the new age
groups directly.
Both studies found a higher degree
of variability in protein expression in the first days and weeks after birth
(Table 4-2). The amount of variability appears to decline somewhat in the older
age groups with the least amount of variability observed in the 10-18 year age
group.[2]
The reason for the high degree of
variability in the 0-7 day age group for the Johnsrud et al. (2003) study
becomes clear when one examines the data in greater detail. Figure 4-2 shows the cumulative distribution
for microsomal CYP2E1 content for this age group. Approximately 30% of the values are at zero
and 80% of the values are below 10 pmol/mg microsomal protein. The authors have suggested that the four
highest values may reflect enzyme induction in utero perhaps as a result of
maternal exposure to CYP2E1-inducing chemical or physiological factors.[3] The high values occurred in infants across
the age range in this group, not just in the oldest infants. The cumulative distributions for the older
age groups followed smoother functions (data not shown).
This in vitro evidence for CYP2E1 is consistent with in vivo clearance data in which
trimethadione was studied across a wide age range beginning with neonates
(Nakamura, et al., 1998). Trimethadione, which was formerly used to treat
epilepsy, is metabolized primarily by CYP2E1 and continues to be used at low
doses to assess hepatic function (Kurata, et al., 1998; Tanaka, et al.,
2000). The very low trimethadione
metabolism rates in neonates seen by Nakamura et al (1998) approached adult
levels in a broad infant age group (one month to one year).
[2] We also estimated the GM and GSDs for the Vieira et
al. data on 6 hyroxychoroxozone formation by CYP2E1. While the developmental profile was similar
(i.e. the ratio of GM in each age group to adult GM), the degree of variability
differed primarily at the two youngest age groups. The GSDs were similar to adult levels for all
age groups. Such differences are a
further reflection of the uncertainty attending use of in vitro data to project in
vivo levels of inter-individual variability.
[3] Personal communication with Ron Hines.
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