Liver toxins

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

Di-tt-octylphthalate has been shown to be a mild liver toxin at high doses in acute- and intermediate-duration studies in rodents. While the mechanism of action for these hepatic effects is not known, di-w-octylphthalate does not appear to behave like other phthalate esters such as di(2-ethylhexyl)phthalate, which have been shown to be hypolipidemic peroxisome proliferators. Instead, the liver changes associated with exposure to di- -octylphthalate are characterized by marked centrilobular accumulation of fat and loss of glycogen, accompanied by reduced glucose-6-phosphatase activity and some centrilobular necrosis. 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

Toxieology. Acetamide is a mucous membrane irritant, a liver toxin, and a carcinogen in animals. 

Toxicology. 1,2-Diphenylhydrazine is a liver toxin in rodents and appears to be carcinogenic in experimental animals. 

Toxicology. 7V-nitrosodimethylamine (DMN) is a liver toxin and is carcinogenic in many species of test animals. 

Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, parenteral silybin is nevertheless marketed and used in Europe as an antidote in Amanita phalloides mushroom poisoning. This use is based on favorable outcomes reported in case-control studies. 

Liver toxin and animal liver carcinogen Monocrotaline. Toxic alkaloid present in certain Crotalaria plants... 

A mercurated furan has been studied the relevant dimensions of the sheep liver toxin derivative are shown in (35). It is obvious that the metal causes some deformation, though not much, which is distributed around the ring. The methyl group is pushed away from the metal and the C(2)—C(3)—Me angle widens the furan ring is not exactly planar though it is nearly so (74JOC3392). 

The most common source of aflatoxins is moldy food, particularly nuts, some cereal grains, and oil seeds. The most notorious of the aflatoxins is aflatoxin B1( for which the structural formula is shown in Figure 19.1. Produced by Aspergillus niger, it is a potent liver toxin and liver carcinogen in some species. It is metabolized in the liver to an epoxide (see Section 7.3). The product is electrophilic with a strong tendency to bond covalently to protein, DNA, and RNA. Other common aflatoxins produced by molds are those designated by the letters B2, G1( G2, and M,. 

A commercial synthesis (Albemarle) of naproxen (a 2-aryl propionic acid anti-inflammatory related to ibuprofen) involves palladium catalyzed hydroxycarbonylation of an aryl olefin which is itself made in a palladium catalyzed Heck coupling reaction (Figure 6b). Resolution is needed to obtain the (5)-enantiomer of naproxen since its optical isomer is a liver toxin. 

Both liver and kidney systems are affected by a variety of secondary metabolites, and the pyrrolizidine alkaloids have been discussed earlier (Tables IV and V). The alkaloids are activated during the detoxification process, and this can lead to liver cancer. Also, many other enzyme or metabolic inhibitors (e.g., amanitine), discussed previously, are liver toxins. 

Penicilhc acid (fig. 5), also a metabolite of many Penicillium and Aspergillus species, is a contaminant of com ( blue eye com ), beans and even meat. Even though penicilhc acid has been shovm to be a liver toxin, no instances of animal or human toxicity have been reported. In spite of this, the potential for these toxins to act synergistically with other more potent toxins is a concern since the species that produce these toxins usually produce other toxins as well [71]. 

S)-Naproxen is the aaive ingredient in the widely used pain relievers Naprosyn and Aleve. The three-dimensional orientation of two atoms at a single carbon in naproxen determines its therapeutic properties. Changing the position of these two atoms converts this anti-inflammatory agent into a liver toxin. In Chapter 5 we learn more about stereochemistry and how small structural differences can have a large effect on the properties of a molecule. 

The S enantiomer of naproxen, the molecule that introduced Chapter 5, is an active antiinflammatory agent, but the R enantiomer is a harmful liver toxin. Changing the orientation of two substituents to form a mirror image can thus alter biological activity to produce an undesirable side effect in the other enantiomer. 

Besides beginning with a nonrenewable chemical feedstock, adipic acid synthesis has other problems. The use of benzene, a carcinogen and liver toxin, is undesirable, especially in a large-scale reaction. Moreover, oxidation with HNO3 in Step [3] produces N2O as a by-product. N2O depletes ozone in the stratosphere in much the same way as the CFCs discussed in Chapter 15. In addition, N2O also absorbs thermal energy from the earth s surface like CO2, and may therefore contribute to global warming, as discussed in Section 4.14. 

A liver-protective preparation must therefore be capable of protecting the hepatocytes (as well as the sinus endothelium) from a particular liver toxin, or from 2 or 3 clearly defined (or, in the optimal case, all obligate) liver toxins, by administration before or, at the latest, when the damage occurs. The use of a substance in existing cellular damage would be classified as therapy and no longer protection . The term protective liver therapy clearly implies prophylaxis - which, apart from the above exceptions (e. g. vaccination), is usually not feasible under the provisions of the respective health insurance system. (12)... 

Liver toxins acetaminophen, hydrazine, allyl alcohol, thioacetamide, a-naphthylisothiocyanate, and carbon tetrachloride. 

The liver is essential in order to maintain life. Accordingly, xenobiotic attacks on it threaten life and well-being. Many chemicals are hepatotoxic, but mixtures of lipophilic and hydrophilic chemicals are liver toxins at exposure levels that are often far below those that are toxic for the single chemicals in those mixtures. Animal studies have demonstrated the... 

Some effects of mixtures may become predictable, particularly in simple binary mixtures. For example carbon tetrachloride reacts synergistically with both ethanol and isopropanol as a liver toxin. Predictability is less reliable in complex mixtures that are prevalent in most environmental exposures. ... 

A wide range of toxins has now been investigated including the kidney cortical toxins mercury chloride, - p-aminophenol, " ifosfamide, the kidney medullary toxins propyleneimine and 2-bromoethanamine hydrochloride and the liver toxins hydrazine, allyl alcohol, thioacetamide and carbon tetrachloride. The testicular toxin cadmium chloride has also been investigated in detail. The aldose reductase inhibitor HOE-843 has also been studied. ... 

Fig. 3. A plot of principal component scores (PCI versus PC2) for a set of rat urine samples using simple scored levels of 16 metabolites as the descriptor set. A cluster of renal cortical toxins is seen at the left, whilst the testicular and liver toxins are to the right. At the bottom the two renal papillary toxins (BEA = 2-bromoethanamine and PI = propyleneimine) appear to cluster with liver toxins (ALY = allylalcohol and ANIT = o-napthylisothiocyanate) but are well separated in the third principal component.

Collectively, these data clearly indicate that the liver is a target for hydrazine and 1,1-dimethylhydrazine toxicity. Furthermore, species differences are apparent in the sensitivity to hepatotoxicity. However, these data are inconsistent (mice were the most sensitive in one study but the most resistant in another) and suggest that strain differences in sensitivity may also exist in mice. It should be noted that dimethylnitrosamine, a potent liver toxin, occurs as a contaminant of technical grades of... 

Safety note Dichloromethane is effectively non-flammable and is often the solvent of choice, but it is a liver toxin and an irritant, and must be handled in the fume cupboard if volumes greater than 50 mL are to be used. 

Gyromitrin is a volatile derivative of hydrazine (see Figure 4) with the chemical formula of acetaldehyde methyl formylhydrazone and is readily converted to N-methyl-N-formyl hydrazine and N-methylhydrazine. It is primarily a liver toxin although the red blood cells and central nervous system are also involved. The... 

Well water contains 1,2-dibromoethane at. 002 mg/L at and carbon tetrachloride at. 003 mg/L. Both are liver toxins, therefore they will be added together using the Hazard Index formula. The EPA RfDs can be used as the health-based standard. Eor 1,2-dibromoethane it is 9 X 10 mg/kg/day and for carbon tetrachloride it is 7 X 10 " -mg/kg/day. 

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