Enzymic differentiation of human liver: Comparison with the rat model

Summary: The quantitative pattern of enzymes in the second trimester human fetal liver is significantly different from that of adult liver. For some 20 enzymes, the activity quotient (AQ, i.e., activity of immature liver divided by that in adult liver) is appreciably different from 1.0. Most of the enzymes increase their concentrations with age but, as one would expect, some contribute to differentiation by diminishing in amount. In developing human liver the concentrations of the various enzymes tend to change in the same direction as they do in rat liver. Those that increase in rat liver have been classified into three main clusters, according to whether their rise begins on about the 17th day of gestation (B), the first neonatal day (C), or just before weaning (D), respectively. The distribution of these enzymes among these three clusters correlates with their AQ’s in the human fetal liver. In general, enzymes with AQ around 0.5 belong to cluster (B) in rat liver whereas those with 0-0.16 belong to cluster C or D. Gross malformations resulting from the teratogenic action of drugs, hormones, or vitamins on the early embryo attract much attention. The harmful impacts of such agents at late stages of gestation are less spectacular. They may be more frequent, however, and manifest themselves in permanent inadequacies in metabolism or growth with a tendency to succumb to minor childhood diseases. The underlying causes may not be mirrored in the cytocomposition or even the subcellular morphology of autopsy specimens. Only deviations from the organ characteristic quantitative pattern of gene products would provide sensitive enough indictors of the metabolic lesions and of the aberrant aspects of differentiation that were responsible for them. In both the presence and absencc of detectable morphologic abnormalities, the study of enzymes, this most varied and largest class of specific chemical constituents, would greatly extend the resolving power of the usual diagnostic procedures postmortem. Speculation: The sequence in which different enzymes approach their adult concentration in human liver closely resembles that in rat liver. This suggests that the mechanisms responsible for the schedule of gene expression must also be analogous: the synthesis of specific groups of enzymes at each corresponding critical period is regulated by the same hormones in both species. Hence, the “enzyme pathology” of infant livers not only specifies basic metabolic lesions: aided by observations on the rat model, it could also identify the age of onset and the kind of aberrations in the fetal environment which initiated the lesions.