Gonzalez F J
National Cancer Institute, National of Health, Bethesda, MD 20892, USA.
Toxicol Lett. 1998 Dec 28;102-103:161-6. doi: 10.1016/s0378-4274(98)00302-6.
Most of the chemicals that cause toxicity in animals are metabolized and this metabolism can either increase or decrease the extent of toxicity. A large number of enzymes are involved in the metabolism of xenobiotics. Cytochromes P450 are among the most important and these enzymes are primarily involved in metabolic activation through oxidative metabolism. Transferases, including the glutathione S-transferases, N-acetyltransferases, UDP-glucuronosyltransferases, microsomal and cytosolic epoxide hydrolases, and NAD(P)H quinone oxidoreductase are also significant in xenobiotic metabolism and can play a role in chemical sensitivities. Polymorphisms in P450s and transferases have been found in experimental animals and humans in which a certain segment of the population, usually greater than 1%, are lacking expression of a particular enzyme. In humans, polymorphisms have been associated with adverse drug reactions but have not been shown to cause any serious developmental or physiological defects thus suggesting that in mammals, xenobiotic-metabolizing enzymes may only be required for metabolism of foreign chemicals and have no other critical role. To determine the roles of xenobiotic-metabolizing enzymes in mammalian development and physiological homeostasis, and in sensitivities to chemical toxicity and carcinogenesis, targeted gene disruption was carried out to produce gene knockout mice. Several lines of mice were produced and characterized and these are discussed.
大多数导致动物中毒的化学物质会被代谢，这种代谢既可能增加也可能降低毒性程度。大量酶参与外源性物质的代谢。细胞色素P450是其中最重要的酶，这些酶主要通过氧化代谢参与代谢活化。转移酶，包括谷胱甘肽S -转移酶、N -乙酰转移酶、尿苷二磷酸葡萄糖醛酸转移酶、微粒体和胞质环氧化物水解酶以及NAD(P)H醌氧化还原酶在外源性物质代谢中也很重要，并且可能在化学敏感性方面发挥作用。在实验动物和人类中发现了P450和转移酶的多态性，其中某一特定人群（通常超过1%）缺乏特定酶蛋白的表达。在人类中，多态性与药物不良反应有关，但尚未显示会导致任何严重的发育或生理缺陷，因此表明在哺乳动物中，外源性物质代谢酶可能仅对外来化学物质的代谢是必需的，并无其他关键作用。为了确定外源性物质代谢酶在哺乳动物发育和生理稳态以及对化学毒性和致癌作用的敏感性中的作用，进行了靶向基因敲除以产生基因敲除小鼠。已培育并鉴定了多个品系的小鼠，并对其进行了讨论。
