PubMed · 7110386
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A G Hanselaar, E J Ariëns, P T Henderson, A M Simonis. 1982-05-29. [Hidden formaldehyde].. https://pubmed.ncbi.nlm.nih.gov/7110386/
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Trichochromes, the peculiar pigments of red human hair, featuring the Delta(2,2)(')-bi(2H-1,4-benzothiazine) skeleton, are known to arise from cysteinyldopas, mainly the 5-S-isomer (5). However, the mode of formation and the direct precursors have remained largely undefined. To fill this gap, we investigated the oxidation of 5 in air or with chemical and enzymatic agents under biomimetic conditions. In the presence of zinc ions, which occur in epidermal tissues at significant concentrations, the reaction course is diverted toward the formation of a labile 3-carboxy-2H-1,4-benzothiazine intermediate (11), which was identified by direct NMR analysis. Structural formulation was supported by characterization of the analogous compound 13 isolated from oxidation of the model 5-methyl-3-S-cysteinylcatechol (12) after methylation. In the further stages of the oxidation, diastereomeric 2,2'-bi(2H-1,4-benzothiazine) 15 and 14 were obtained from 5 and 12, respectively, the reaction proceeding at a higher rate and to a greater extent in the presence of acids. The dimers were shown to readily convert to each other in the presence of acids. In the case of the methylated dimers 14, a 2,2'-bi(4H-1,4-benzothiazine) intermediate (16) was isolated and characterized. In acidic media, trichochrome C (1a), the most abundant in red human hair, was smoothly formed from aerial oxidation of 15, and under similar conditions, trichochrome-related products (17 and 18) were obtained from 14 prior to or after methylation. The presence of 1a and precursors 5 and 15 was investigated by HPLC analysis of red hair samples following mild proteolytic digestion. On the basis of these data, a likely biosynthetic route to trichochrome pigments of red human hair is depicted.
Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair per se provide an immediate growth advantage. According to the 'associated-selection' model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The 'associated-selection' model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed.
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