Enzymic Differentiation of Human Liver: Comparison with the Rat Model

Abstract

The cluantitative pattern of enzymes in the seconcl trimester h u~n a n fetal liver is sigllificantly different fro111 that of aclult liver.For some 20 enzymes, the activity quotient (AQ, i.e., activity of i n~n~a t u r e liver divicled by that in atlult liver) is appreciably different front 1.0. RIost of the enzynles increase their concentrations with age but, as one would expect, sollie contribute to differentiation by tlin~inishing in amount.In cleveloping hurnan liver the concentrations of the various enzynles tend to change in the sanle clirection as they d o in rat liver. 'I'hose that incriase in rat liver have been classifietl into three tnain cIu~ters, accortling to whether their rise begins o n about the 17th day of gestation (B), the first neonatal day (C), or just before weaning (D), respectively. The distribution of these enzynles anlong these three clusters correlates with their AQ's in the hutnan fetal liver. 111 general, enzyrnes with A Q around 0.5 belong to cluster (B) in rat liver whereas those with 0-0.16 belong to cluster C or D.Gross n~alforn~ations resulting fro111 the teratogenic action of drugs, hormones, or vitaniins on the early enlbryo attract n~ucll attention. The harn~ful in~pacts of such agents at late stages of gestation are less spectacular. 'They rnay be more frequent, however, ant1 inanifest then~selvcs in perlnanent inatlecluacies in n~etabolisn~ or growth with a tendency to succun~b to minor childhood cliseases. The underlying causes nlay not be n~irrored in the cytocolnposition or even the subcellular nlorphology -of autopsy specimens. Only deviations from the organ characteristic quantitative pattern of gene products woulcl provide sensitive enough inclictors of the metabolic lesions and of the aberrant aspects of differentiatiol~ that were responsible for them. In both the presence ancl absence of detectable ~norphologic abnornlalities, the stutly of enzymes, this rnost varied and largest class of specific chen~ical constituents, would greatly extend the resolving power of the usual diagnostic procedures postmortem. SpeculationThe sequence in which clifferent enzymes approach their adult concentration in human liver closely resembles that in rat liver.'I'his s~~g g e s t s that the n~echanislns responsible for the scheclule of gene expression rnust also be analogous: the synthesis of specific groups of enzynles at each correspondir~g critical period is regulated by the sarne horniones in both species. Hence, the "cnzyn~e pathology" of infant livers not only specifies basic n~etabolic lesions: aidecl by observations on the rat ~noclel, it coultl also identify the age of onset and the kind of aberrations in the fetal environment which initiated the lesions.

Urinary Excretion of Vitamin K Metabolites in Term and Preterm Infants: Relationship to Vitamin K Status and Prophylaxis

“…Neonatal concentrations of the hepatic enzymes ␥-glutamyl carboxylase (GGCX) and vitamin K 1 2,3-epoxide reductase (VKOR) may also be suboptimal (5), thus preventing efficient recycling of vitamin K (6). This premise is supported by the known immaturity of other hepatic enzyme systems in this population (7). In some infants, a nutritional lack of vitamin K, sometimes combined with pathological factors, results in a potentially life-threatening bleeding disorder known as vitamin K deficiency bleeding (VKDB) (8).…”

Enzyme Activities of the Mitochondrial Energy Generating System in Skeletal Muscle Tissue of Preterm and Fullterm Neonates

“…Differentiation of the enzymes for the mitochondrial oxidative system has been shown in man as well as in animals not only for muscle but also for other tissues such as brain, liver and kidney. [22][23][24][25] The results of this study indicate that agematched reference values are required for adequate diagnosis of mitochondrial encephalomyopathies. Patients with mitochondrial defects may present in the neonatal period.I" and enzyme deficiencies have to be discriminated from the low control values of this period.…”

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

“…Under the classification system originally proposed by Greengard (1969Greengard ( , 1977, where class I is "higher in fetal life," class II is "constant throughout life," and class III is "develops after birth," we suggest that NQO1 be classified as a class II ontogenetic enzyme in the human liver. Notably, Greengard (1969Greengard ( , 1977 primarily described and investigated metabolic enzymes involved in biochemical pathways such as gluconeogenesis and glycolysis, with very few studies on xenobiotic-metabolizing enzymes. Her classifications primarily revolved around cross-species comparisons.…”