Enzymes tissue metabolism

Vertebrate liver is a very rich source of enzymes that metabolize lipophilic xenobiotics, and subcellular fractions are prepared to study metabolism. Sometimes, other tissues such as brain, kidney, testis, and ovary are also treated in this way. A typical subcellular fractionation of liver might be as follows ... 

Many reports on the effects of ozone and PAN on physiologic processes (net photosynthesis, stomatal response, and water relations) and on metallic activity (including in vivo and in vitro studies of individual enzymes, enzyme systems, metabolic pathways, metabolic pool relationships, cell organelles, and plant tissue studies) have appeared since 1964. 

Still another experimental route to introducing otherwise excluded molecules into the brain is to chemically modify them so that they are lipophilic and therefore can passively diffuse. The brain, just as most other organs and tissues of the body, has enzymes to metabolize or biotransform metabolites in order to use and then get rid of them. Many of these pathways are oxidative. A reduced species or derivative which is lipophilic can enter the brain by simple passive diffusion there to be oxidatively transformed into an active state. Compounds which have been tested in animals include derivatives of 2-PAM (an antidote for organophosphate insecticide poisoning) and phenylethylamine (similar to amphetamine type molecules). Figure 5 illustrates the general concept behind this method. 

Tissue lysate (or homogenates), post-mitochondrial supernatants and microsomes offer several practical advantages for the study of xenobiotic metabolism. The principal advantages are that the human tissues provide a complete system containing all the enzymes in ratios found in vivo, and tissue fractions are stable in relatively long-term storage. Within the different types of tissue fractions, microsomes provide an enrichment of the membrane-bound enzymes, and post-mitochondrial supernatants provide a means to study both membrane-bound and soluble enzymes. Tissue fractions are easily prepared from a variety of tissues including human liver and can be cryopreserved for several years. This allows detailed characterization of the tissue prior to use with xenobiotics of unknown routes of metabolism... 

Whether the toxic effects are mainly due to anemic hypoxia or to the histotoxic effects of carbon monoxide on tissue metabolism is a source of controversy. Carbon monoxide will certainly bind to myoglobin and cytochromes such as cytochrome oxidase in the mitochondria and cytochrome P-450 in the endoplasmic reticulum, and the activity of both of these enzymes is decreased by carbon monoxide exposure. However, the general tissue hypoxia will also decrease the activity of these enzymes. 

Pharmacokinetics Both T4 and T3 are absorbed after oral administration. T4 is converted to T3 by one of two distinct deio-dinases, depending on the tissue. T3 combines with a receptor to stimulate subsequent protein synthesis necessary for normal metabolism. The hormones are metabolized through the microsomal P-450 system. Drugs such as phenytoin, rifampin, phe-nobarbital, etc. that induce the P-450 enzymes accelerate metabolism of the thyroid hormones. 

Methoxyethanol is rapidly absorbed through the skin and lungs into the blood. Its water solubility favors distribution to all body tissues except adipose tissue. Metabolism occurs via two pathways. Methoxyethanol is a substrate for alcohol dehydrogenase, and the resultant methoxyacetaldehyde is metabolized to methoxyacetic acid by aldehyde dehydrogenase. In rats, pretreatment with phenobarbitol decreased formation of methoxyacetaldehyde but accelerated formation of methoxyacetate in liver cytosolic fractions. A minor pathway involves demethylation by undefined enzymes to ethylene glycol and CO2. 

The metabolism of n-3 and n-6 PUFAs is interlinked, as they compete for enzymes and metabolic substrates at all levels. Therefore, relative as well as absolute dietary intake is relevant in the determination of tissue n-3 and n-6 fatty acid levels. The Western diet typically contains high levels of n-6 fatty acids, as these are components of most animal and vegetable fats. Dietary sources of n-3 PUFA are varied. The most plentiful sources are fish, shellfish, and marine products, which contain large amounts of EPA and DHA. Certain plant oils, such as rapeseed (canola), soybean, and perilla contain large amounts of LNA (Crawford Sinclair, 1972 Sinclair, 1975). Although beef and lamb do contain n-3 PUFAs, both the absolute content and the n-3 n-6 ratio of PUFAs within these meats is low. 

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