Liver inducing chemicals

Lymphocytic Tumors of Thymic Origin. The appearance of spontaneous tumors (e. . SAKRTLS-13) in AKR and C58 mice (27) is quite common. Other thymic tumors can also be induced chemically (28) (BALENTL—3, -5 or P-1798 Table I) or virally (Moloney leukemia virus (29)). in the early stage of tumor development they are confined to the thymus, but later the tumor is metastasized to the spleen, liver, kidney, and lymph nodes. 

The use of chick embryo liver culture in vitro as contrasted to induction in the whole animal permitted the inference that the inducing chemicals acted directly on the hepatic cells and not via other stimuli generated from other organs. The porphyrins formed could be seen by fluorescence microscopy to accumulate in the c)doplasm of the liver parenchyma cells and were identified mainly as coproporphyiin with some protoporphyrin [25]. However, Doss [70] found mainly protoporphyrin. This difference may depend on conditions of culture the older cultures had more coproporphyrin and uroporphyrin. The increase in porphyrins in tissue culture has been assumed to be a result of an increase in ALA-synthetase. With the aid of 13-cm-diameter petri dishes, it has been possible to grow sufficient numbers of cells and demonstrate with inducing chemicals an increase in vitro of ALA-synthetase activity of seven to ten times that of controls, in a 20-hour period [21]. 

The chemicals induce only in liver, not in other tissues. The steroids, as will be discussed later, induce ALA-synthetase in liver cells as well as in erythroid cells of the chick blastoderm. Although the kidneys of the chick embryo may rapidly convert ALA to porphyrins, neither steroids nor other inducing chemicals have an inducing effect on this tissue. Thus, response to inducing compounds depends on the tissue. In the liver, at least of the chick embryo, both steroids and other chemicals induce in erythropoietic blastoderm only steroids induce and in kidneys and other tissues none of these compounds induce. Steroid induction in liver and erythropoietic tissue appears to involve a transcriptional mechanism induction by chenucals appears to involve mainly the translational mechanism (see Section V). 

ALA-synthetase has one of the shortest half-lives yet reported for any mammalian liver enzyme, even the inducible ones. In contrast, the half-lives of two other mitochondrial enzymes, alanine and ornithine-amino transferases, inducible by the corticosteroid prednisolone acetate in a concentration of 0.5 mg/rat/day was 17 to 24 hours [75]. The short half-life of ALA-synthetase apparently depends on other cell constituents. When mitochondria from induced guinea pigs were isolated, the activity of their ALA-synthetase was maintained constant over a period of at least 5 hours [35] this activity may have finally not been limited by the stability of the enzyme itself but by the succinyl-CoA-synthesizing mechanism of the mitochondria. These facts suggest that there may be an active process of ALA-synthetase destruction which occurs in the cells but not necessarily in the isolated mitochondria, and which is not affected by the inducing chemicals such as DDC or AIA. 

In this section, the activities of inducing chemicals are discussed in relation to their destruction by the liver microsomal oxygenase system the rate of heme synthesis and breakdown is considered in relation to the inhibitory properties of heme on the synthesis of ALA-synthetase and the contrasting effects of glucose and starvation are summarized in relation to their effects on induction. 

A. Inducing Chemicals and the Microsomal Oxygenase System of the Liver... 

The inducing effect of chemicals that bring about a three- to four-fold increase in liver ALA-synthetase in 6 hours was found by Marver [109] to be nullified if simultaneously with the inducing chemical the large dose of 12 mg of hemin chloride (per 100 gm wt) was injected into the rat. 

In rats, ferric citrate [128], hydrocortisone, and triiodothyronine [125] do not induce but enhance the induction of inducing chemicals. Ferric citrate in chick embryo liver culture behaves similarly [67a]. 

The hazards of chemicals are commonly detected in the workplace first, because exposure levels there are higher than in the general environment. In addition, the exposed population is well known, which allows early detection of the association between deleterious health effects and the exposure. The toxic effects of some chemicals, such as mercury compounds and soot, have been known already for centuries. Already at the end of the eighteenth century, small boys who were employed to climb up the inside of chimneys to clean them suffered from a cancer of the scrotum due to exposure to soot. This was the first occupational cancer ever identified. In the viscose industry, exposure to carbon disulfide was already known to cause psychoses among exposed workers during the nineteenth century. As late as the 1970s, vinyl chloride was found to induce angiosarcoma of the liver, a tumor that was practically unknown in ocher instances. ... 

Ulll TABLE S. 14 Chemical Compounds that Induce Chronic Liver Damage... 

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

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