Levine W G
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
Drug Metab Rev. 1991;23(3-4):253-309. doi: 10.3109/03602539109029761.
Azo dyes are consumed and otherwise utilized in varying quantities in many parts of the world. Such widely used chemicals are of great concern with regard to their potential toxicity and carcinogenic properties. Their metabolism has been studied extensively and is significant for detoxication and metabolic activation. Both oxidative and reductive pathways are involved in these processes. The majority of azo dyes undergo reduction catalyzed by enzymes of the intestinal microorganisms and/or hepatic enzymes including microsomal and soluble enzymes. The selectivity of substrate and enzyme may to a large extent be determined by the oxygen sensitivity of reduction since a normal liver is mainly aerobic in all areas, whereas the microorganisms of the lower bowel exist in an anaerobic environment. However, it should be pointed out that the pO2 of centrilobular cells within the liver is only a fraction that of air, where pO2 = 150 torr. Therefore, an azo dye reduction experiment performed aerobically may not be an accurate predictor of reductive metabolism in all areas of the liver. Many of the azo dyes in common use today have highly charged substituents such as sulfonate. These resist enzymic attack and for the most part are poorly absorbed from the intestinal tract, providing poor access to the liver, the major site of the mixed-function oxidase system. Lipophilic dyes, such as DAB, which are often carcinogenic, readily access oxidative enzymes and are activated by both mixed-function oxidase and conjugating systems. Reduction of the carcinogenic dyes usually leads to loss of carcinogenic activity. By contrast, most of the highly charged water-soluble dyes become mutagenic only after reduction. Even then, most of the fully reduced amines required oxidative metabolic activation. An outstanding example is the potent human bladder carcinogen benzidine, which derives from the reduction of several azo dyes. Many problems regarding mutagenic and carcinogenic activation remain to be solved. At the present time, it is apparent that both oxidative and reductive pathways yield toxic products. Toxicologic assessment of azo dyes must consider all pathways and particularly the oxygen sensitivity of azoreduction. This is critical in the treatment of waste from chemical plants where there is a great need for soil bacteria which catalyze reduction aerobically. Consideration of secondary pathways are also of great concern. For example, azoreduction of carcinogenic dyes such as DAB removes carcinogenic activity although oxidative metabolism of the primary amines yield mutagenic products. Such apparent dilemmas must be dealt with when considering metabolism/toxicity relationships for azo dyes.
偶氮染料在世界许多地区被大量使用和以其他方式利用。这类广泛使用的化学品因其潜在的毒性和致癌特性而备受关注。它们的代谢已得到广泛研究，并且在解毒和代谢活化方面具有重要意义。氧化和还原途径都参与了这些过程。大多数偶氮染料在肠道微生物酶和/或肝脏酶（包括微粒体酶和可溶性酶）的催化下发生还原反应。底物和酶的选择性在很大程度上可能由还原反应对氧气的敏感性决定，因为正常肝脏在所有区域主要是有氧环境，而肠道下段的微生物存在于厌氧环境中。然而，应该指出的是，肝小叶中心细胞内的pO2仅为空气中pO2（150托）的一小部分。因此，需氧条件下进行的偶氮染料还原实验可能无法准确预测肝脏所有区域的还原代谢情况。如今常用的许多偶氮染料都带有高电荷取代基，如磺酸根。这些基团能抵抗酶的攻击，并且在很大程度上难以从肠道吸收，因而难以进入混合功能氧化酶系统的主要场所——肝脏。亲脂性染料，如通常具有致癌性的二氨基联苯（DAB），很容易接触到氧化酶，并被混合功能氧化酶和结合系统激活。致癌染料的还原通常会导致致癌活性丧失。相比之下，大多数高电荷水溶性染料只有在还原后才会变得具有致突变性。即便如此，大多数完全还原的胺仍需要氧化代谢活化。一个突出的例子是强效的人类膀胱癌致癌物联苯胺，它是由几种偶氮染料还原产生的。关于致突变和致癌活化仍有许多问题有待解决。目前，很明显氧化和还原途径都会产生有毒产物。对偶氮染料的毒理学评估必须考虑所有途径，尤其是偶氮还原对氧气的敏感性。这在处理化工厂废物时至关重要，因为非常需要能在需氧条件下催化还原反应的土壤细菌。对次要途径的考虑也备受关注。例如，致癌染料如DAB的偶氮还原消除了致癌活性，尽管一级胺的氧化代谢会产生致突变产物。在考虑偶氮染料的代谢/毒性关系时，必须处理好这类明显的困境。
