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Defense and Clearance



In organisms, there are always some nonnutritive substances from external environment or produced by the body itself. They can’t be either transformed into cellular components or employed as energy source. Some of them are physiologically or pathologically active substances, and some are even harmful constituents with toxicological activity. Many of these substances are liposoluble and they often need to undergo some biochemical transformation in the body, to enhance their polarity and increase their water solubility. Therefore, they can be excreted or transformed into physiological, pathological or toxicological components to take effect in the body. The conversion reactions include oxidation, reduction, hydrolysis, and so on, which are called first phase reactions. The polarity of some substances can be greatly changed to meet the above requirements through first phase reaction, while some others must be put into the second phase reaction, so that it can be combined with an extremely polar compound to increase its solubility. Enzymes involved in the two-phase reaction, especially the enzymes in the first phase reaction, are mostly present in the endoplasmic reticulum.

Characteristics

Transformation and detoxification of exogenous substances in vivo through enzyme have two distinctive characteristics. One is the independence of reaction. For example, the sedative drug chlorpromazine can independently perform N-oxidation, N-dealkylation, hydroxylation, and conjugation under the action of the corresponding enzyme. Another one is the continuity of reaction, which is achieved by a combination of multiple enzymes.

Participation Type of Enzymes

The enzyme involved in clearance and defense work may be a single enzyme, such as superoxide dismutase, which directly removes highly reactive superoxide ions and prevents the production of lipid peroxides. Restriction endonuclease also selectively hydrolyzes heterologous DNA of invading phages.

It is also possible to participate in this procedure in a form of complex that is made up of several enzymes. For instance, lysosomal hydrolases produced by ribosomes are concentrated and packaged by Golgi to form primary lysosomes, which then combines with the phagosome or autophagesome to generate a secondary lysosome. The term "phagosome" refers to a particle formed by pinocytosis or phagocytosis of an exogenous substance, and an autophagic vesicle means a particle coated by its own waste.

An enzyme system may also involve in the task, such as thrombin system, hemolytic cell protease system, and complement system in the immune system, all of which play their roles through a cascade of enzymes. There are also drug-converting enzyme systems based on the endoplasmic reticulum.

Classic Examples

Oxidative enzyme system is representative. Most of the exogenous lipophilic substances are generally oxidized by the electron transport chain involved with NADPH in the endoplasmic reticulum of hepatocytes. These electron transfer oxidative enzymes account for almost one-fifteenth of the composition of the endoplasmic reticulum membrane, and the composition is quite complicated. Monooxygenase, also known as mixed function oxidase, is a hydroxylase system composed of cytochrome P-450 and cytochrome b5. It plays a very important role in drug metabolism. Separation of these proteins requires treatment with detergents like Renex 690 or proteases.

Defense and Clearance

Another typical example is glucuronyltransferase. There are roughly six types of second phase reactions in vivo: glucuronic acid binding, thioetherine formation, sulfate formation, hippuric acid formation, acetylation and methylation. It is the glucuronyltransferase in the endoplasmic reticulum that catalyzes glucuronide conjugation by transferring glucuronyl group of uridine diphosphate glucose (UDPG) to various receptors. This reaction is irreversible. Glucuronyltransferase is present in many tissues of mammals such as renal cortex and digestive tract. However, the endoplasmic reticulum of liver is the most important place for the transformation and clearance of exogenous substances. The enzyme has certain specific requirements for the substituents of the substrate, which can be hydroxyl group, carboxyl group, thio group, amino group, imino group, aromatic group, hydrocarbon groups, and heterocyclic compound. Therefore, the glucuronyltransferases in endoplasmic reticulum are a family with different substrate specificities. However, this enzyme is very unstable and often become invalid attributable to the destruction of membrane structure. Before its separation and purification, it is usually treated with a neutral surfactant.


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