Liver compounds

Distribution is the step of toxicokinetics in which a toxicant moves from the site of absorption throughout the body. The toxicant may pass cell barriers, enter the circulation system, or enter the lymphatic system. The distribution mechanism can have profound effects on the action of a toxicant. A substance absorbed through the GI tract will be transported through the portal system to the liver. Compounds absorbed through the lungs, skin, or intravenous injection, however, will immediately enter systemic circulation. These two routes are metabolically distinct, as demonstrated in the next section. 

The behaviour of PCT is similar to that of PCB [68, 118]. Monochlorobenzene and the dichlorobenzenes are sufficiently volatile for inhalation to be a significant route of exposure, at least in the workplace or other indoor atmospheres, they will also be exhaled when exposure ceases. All other compounds are excreted in the urine, after metabolism to hydroxyl compounds, as glucuronide or other conjugates. Metabolism proceeds via an arene oxide (Fig. 3), as a result of mixed function oxidase activity in the liver compounds containing two adjacent unsubstituted carbon atoms form arene oxides most readily. Chlorobenzenes have been shown to be ex-... 

Iodine occurs to a minute extent (less than 0.001 %) in sea water, but is found in greater concentration, combined in organic form, in certain seaweeds, in oysters and in cod livers. Crude Chile saltpetre, or caliche contains small amounts of sodium iodate, NalOj. from which iodine can be obtained (see below). Some insoluble iodides, for example liiose of silver and mercury(II), occur in Mexico. Iodine is found in the human body in the compound thyroxin in the thyroid gland deficiency of iodine in diet causes enlargement of this gland (goitre). 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

Side chain oxidation of alkylbenzenes is important in certain metabolic processes One way m which the body rids itself of foreign substances is by oxidation m the liver to compounds that are more polar and hence more easily excreted m the urine Toluene for example is oxidized to benzoic acid by this process and is eliminated rather readily... 

Many biological processes involve oxidation of alcohols to carbonyl compounds or the reverse process reduction of carbonyl compounds to alcohols Ethanol for example is metabolized m the liver to acetaldehyde Such processes are catalyzed by enzymes the enzyme that catalyzes the oxidation of ethanol is called alcohol dehydrogenase... 

The toxicity of chloronaphthalenes requires that special attention and caution be used during their manufacture and use acne is the most common result of excessive skin exposure to them and the most frequendy affected areas are the face and neck (16). Liver damage has occurred in workers who have been exposed repeatedly to vapors, particulady to those of penta- and hexachloronaphthalene [1335-87-1] (17,18). Uses for the chlorinated naphthalenes include solvents, gauge and instmment duids, capacitor impregnants, components in electric insulating compounds, and electroplating stop-off compounds. 

A comprehensive study of the tolerance of laboratory animals to vapors of 2-nitropropane was reported in 1952 (100). In a study pubHshed in 1979, rabbits and rats survived exposure to nitromethane for six months at 750 and 100 ppm, respectively, with no unexpected findings (101). Similarly, no compound-related effects were found for rabbits exposed to 2-nitropropane at 200 ppm or for rabbits or rats exposed at 27 ppm. Liver damage was extensive in male rats exposed at 207 ppm for six months, and hepatocellular carcinomas were observed. Subsequendy, the International Agency for Research on Cancer (lARC) found that there is "sufficient evidence" to conclude that 2-nitropropane causes cancer in rats but that epidemiologic data are inadequate to reinforce the conclusion in humans (102). The National Toxicology Program also concluded that it "may reasonably be anticipated to be a carcinogen" (103). 

Sotalol is rapidly and almost completely (>90%) absorbed. Bioavahabhity of absorbed dmg is 89—100%. Peak plasma levels are achieved in 2—4 h. Sotalol is 50% bound to plasma proteins. Plasma half-life of the compound is about 5.2 h. No metabolites of sotalol have been identified indicating littie metabolism. The dmg is excreted mainly by the kidneys (80—90%) and about 10% is eliminated in the feces. The plasma half-life is prolonged in patients having renal failure. Kinetics of the compound are not affected by changes in liver function (1,2). Sotalol has ah the adverse effects of -adrenoceptor blockers including myocardial depression, bradycardia, transient hypotension, and proarrhythmic effects (1,2). 

Oxyphenbutazone (712), y-hydroxyphenylbutazone and kebuzone (715) are metabolites of phenylbutazone in liver. The first cited is an equally potent antiinflammatory agent but slightly less toxic. Compounds (711) and (712) are rarely used as analgesics and antipyretics because of their toxicities. The first one is used in therapy of rheumatoid disorders characterized by a lack of detectable antiglobulin and antinuclear antibodies in the serum. The y-hydroxyphenylbutazone has marked uricosuric activity but little antirheumatic effect. Kebuzone (715) is an antiinflammatory agent still widely used in Europe. 

Arsenic and certain compounds Skin, lung, liver - carcinoma... 

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. ... 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Water solubility (polarity) is essential for excretion. Even though lipid-soluble compounds may also be excreted to primary urine, they are usually at least partially reabsorbed. The metabolites formed in the liver and extrahe-patic tissues remain free (i.e., not bound to proteins) and are, therefore, readily excreted. 

Acute Liver Damage Several compounds (e.g., dimethyl iiitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein syndiesis at the translational level, i.e., by inhibiting the addition of new amino adds into the protein chain being sjTithetized. This is not, however, the only mechanism. Ethioiiine is a compound which inhibits protein synthesis bur doe not induce... 

Accumulation of lipids in the liver (steatosis) is one possible mechanism for liver toxicity. Several compounds causing necrosis of hepatocytes also cause steatosis. There are, however, some doubts that steatosis would be the primary cause of liver injury. Several compounds cause steatosis (e.g., puro-mycin, cycloheximide) without causing liver injury. Most of the accumulated lipids are triglycerides. In steatosis, the balance between the synthesis and excretion of these lipids has been disturbed (see Table 5.13). 

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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