Metabolic zoning, in the liver

The hepatocytes, or parenchymal cells, represent about 80% of the liver by volume and are the major source of metabolic activity. However, this metabolic activity varies depending on the location of the hepatocyte. Thus, zone 1 hepatocytes are more aerobic and therefore are particularly equipped for pathways such as the p-oxidation of fats, and they also have more GSH and GSH peroxidase. These hepatocytes also contain alcohol dehydrogenase and are able to metabolize allyl alcohol to the toxic metabolite acrolein, which causes necrosis in zone 1. Conversely, zone 3 hepatocytes have a higher level of cytochromes P-450 and NADPH cytochrome P-450 reductase, and lipid synthesis is higher in this area. This may explain why zone 3 is most often damaged, and lipid accumulation is a common response (see "Carbon Tetrachloride," for instance, chap. 7). 

This is the accumulation of triglycerides in hepatocytes, and there are a number of mechanisms underlying this response as is discussed below (see the sect. "Mechanisms of Toxicity"). The liver has an important role in lipid metabolism, and triglyceride synthesis occurs particularly in zone 3. Consequently, fatty liver is a common response to toxicity, often the result of interference with protein synthesis, and may be the only response as after exposure to hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride. It is normally a reversible response, which does not usually lead to cell death, although it can be very serious as is the case with tetracycline-induced fatty liver in humans. Repeated exposure to compounds, which cause fatty liver, such as alcohol, may lead to cirrhosis. 

Placental synthesis of estrogens. The placenta lacks the key enzyme necessary for formation of estrogens from cholesterol (CYP 17) and relies on androgenic precursors from the maternal and fetal compartments. The major androgen used comes from the fetal zone of the fetal adrenal this is DHEAS, which is also taken up and metabolized by fetal liver into Iba-hydroxy-DHEAS. The placenta converts DHEAS into estrone (E ) and estradiol (E2) and proces.ses 16a-hydroxy-DHEAS into estriol (Ej). Estrogens enter the maternal circulation and appear in maternal urine as conjugated estrogens. 

Strain. By these criteria, methyl methanesulfonate, A -acetoxyfluorenylacet-amide, captan, and others are preferential inhibitors of the pol Ai strain (Tables 7 and 8). On the other hand, streptomycin and chloramphenicol, although they induce lethality in both indicator strains, do not preferentially kill the pol Ar strain (SI = 1.12 and 1.02, respectively). It should be noted that this procedure is compatible with metabolic activation. Thus, the precarcinogens 2-aminofluorene and cyclophosphamide, which require metabolic activation by hepatic enzymes, do not preferentially inhibit the pol Ai strain in the absence of rat liver microsomes, but do so in the presence of this preparation (Tables 7 and 8). This procedure has the added advantage that results obtained by this modified pol Ai assay are expressed quantitatively, rather than as differences in the diameters of the zones of growth inhibition. As will be seen below, this modified procedure greatly increases the usefulness of the pol A assay (Table 9). 

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