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Human CYP2E1 developmental expression: a role in fetal and pediatric susceptibility to toxicants?
Mccarver, D; Johnsrud, EK; Koukouritaki, SB
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CYP2E1 is important in the bioactivation of small molecular weight toxicants such as toluene, benzene and amp; trichloroethylene. Developmental changes in human CYP2E1 expression likely impact susceptibility of the fetus and young child to these compounds. Two previous studies of human CYP2E1 ontogeny yielded conflicting results. To define human hepatic CYP2E1 developmental expression pattern, microsomes were prepared from human liver samples (N = 72 fetal (8-37 wks); 166 postnatal (1 d-18 y)). Samples from subjects likely to have liver disease were excluded. Microsomal CYP2E1 was quantitated by western blot analysis (LOD = 1.0 fmol CYP2E1). Measurable expression was seen in 18/49 2nd trimester and 12/15 3rd trimester fetal samples (medians = 0.35; 6.7 pmol/mg protein, respectively). CYP2E1 increased after birth but was relatively low in the neonatal period. CYP2E1 in neonatal samples was less than that of infants from 1-3 months of age which was less than that of older infants, children and young adults (median (range) = 8.8 (0-70); 23.8 (10-43); 41.4 (18-95), respectively; each p less than 0.001, ANOVA, post-hoc). Beyond 3 months of age, CYP2E1 protein values did not vary by age. At every age, 4-fold or greater intersubject variation was observed. Increasing postnatal age was associated with increasing protein (N = 29, p = 0.001, linear regression), whereas the relationship with increasing GA was less striking (p = 0.07). These data suggest that infants less than 3 months of age may have significantly lower metabolic clearance of CYP2E1 substrates compared to older age groups, This may lead to a protective effect among very young infants exposed to ubiquitous toxicants such as toluene, benzene and trichloroethylene that are bioactivated by this enzyme. We suggest that the 4-fold variation in CYP2E1 protein among all pediatric patients is consistent with either genetic differences or variable protein stabilization by an unknown endogenous substrate.
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