Lesion, biochemical

Mode of Action. The fundamental biochemical lesion produced by arsenicals is the result of reaction between As " and the sulfhydryl groups of key respiratory enzymes such as pymvate and a-ketoglutarate dehydrogenases. 

Mode of Motion. The cyclodienes, like lindane and toxaphene, affect the nerve axon produciag hyperactivity, convulsions, prostration, and death. The biochemical lesion is the competitive inhibition of the y-aminobutyric acid (GABA) neurotransmitter binding site of the nerve axon. Spray workers with lengthy exposure to dieldrin have suffered from prolonged and repeated central nervous system disturbances produciag epileptiform coavulsioas. Similar disturbances occurred ia workers heavily exposed to chlordecoae. 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Peters, R. A. The biochemical lesion in vitamin B1 deficiency. Application of modern biochemical analysis in its diagnosis. Lancet 1 1161-1164,1936. 

It was shown that the first biochemical lesion in the nervous system after OP treatment is significantly depressing of NE in nervous tissue. 

K13. Komrower, G. M., Schwarz, V., Holzel, A., and Golberg, L., A clinical and biochemical study of galactosaemia. A possible explanation of the nature of the biochemical lesion. Arch. Disease Childhood 31, 254-264 (1956). 

However, the use of CAP was soon restricted after its association with bone marrow depression and aplastic anemia. The underlying biochemical lesion is still obscure, and adequate animal models are lacking. Since thiamphenicol, a CAP analogue where the nitro function has been replaced by a MeSC>2 -group, has never been associated with aplastic anemia, Yunis and coworkers suggested that the p-n il.ro group of CAP may be involved in the development of aplastic anemia129,130. 

There are now thought to be several thousand different genetic diseases, about 10% of which have known biochemical lesions. As has already been seen with the thyroid diseases and diabetes, the phenotypic manifestation, hemophilia, for example, may have genetically, biochemically or clinically different causes. Some of the biochemically identified disturbances, such as those affecting glycogen or galactose, have been important in establishing metabolic pathways (see Chapter 4). 

In 1936 Peters introduced the concept of a biochemical lesion as a basis of human disease, an illness attributable to an identifiable biochemical disorder. This idea was very influential in directing the... 

Peters, R.A. (1963). Biochemical Lesions and Lethal Synthesis. Pergamon Press, Oxford. 

T. Noguchi, Y. Hashimoto, H. Miyata, Studies of the Biochemical Lesions Caused by a New Fluorine Pesticide, A-Methyl-AM l-naphthyl)monofluroacetamide , Toxicol. Appl. Pharmacol. 1968, 13, 189-198. 

In addition to the circumstantial iji vivo evidence for fluorocitrate as the ultimate biochemical lesion we desired to demonstrate unambiguously that it was produced as a metabolite of 29-fluorostigmasterol. The toxicity of fluorocitrate and the resulting lethal accumulation of citrate in mouse, fly and cockroach tissues have been shown in early experiments with fluoroacetamide and fluoroacetate(24). However, to our knowledge, complete characterization of (2R,3R)-2-fluorocitrate as the lethal metabolite in vivo has not previously been reported. We thus prepared( ) [29- ]-29-fluorostigmasterol, [29- H]-29-Huorositosterol and [16- H]-16-fluorohexadec-9-enoic acid to enable isolation of [2-3H]-2-fluorocitrate from vivo incubations using Manduca sexta. 

S. M. Stahl, L. Palazidou (1986). The pharmacology of depression studies of neurotransmitter receptors lead the search for biochemical lesions and new drug therapies. Trends Pharmacol. Sci. 7 349-354. 

Biochemical lesions that induce depressive syndromes include such classic examples as Parkinson s and Huntington s diseases, especially early in their courses. These disorders involve derangements of central amine systems (i.e., in Parkinson s, there is a disturbance in both dopamine and norepinephrine in Huntington s, dopamine is affected, as well as other nonbiogenic amine neural circuits). Furthermore, antidepressants and ECT, which potentiate central neurotransmission, have effectively relieved depression associated with Parkinson s disease. 

Monofluoroacetic acid (fluoroacetate) (Fig. 7.61) is a compound found naturally in certain South African plants, which causes severe toxicity in animals eating such plants. The compound has also been used as a rodenticide. The toxicity of fluoroacetate was one of the first to be studied at a basic biochemical level, and Peters coined the term "lethal synthesis" to describe this biochemical lesion. 

Chitin Synthesis Inhibitors. These are insect growth regulators that prevent the formation of the insect chitinous exoskeleton and thus produce a critical biochemical lesion during hatching, ecdysis, or pupation (44). These complex biochemical and physiological processes are unique to arthropods therefore, the benzoyl phenyl ureas are highly specific insecticides (44). 

Other people cannot understand why the Schizophrenic is so fast or so slow, so ambitious or so lazy, so happy or so sad, etc. First of all, the disease is not caused by the environment. It is caused by a biochemical lesion and has an inheritance factor. This does not mean that the environment is not important. It becomes more so. 

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