Metabolism of foreign compounds

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reaction, classically referred to as phases one and two. Phase I is a... 

R. R. Scheline, Metabolism of foreign compounds by gastrointestinal microorganisms, Pharmacol, Rev., 25,... 

Dougherty, K.K., Spilman, S.D., Green, C.E., Steward, A.R. and Byard, J.L. (1980). Primary cultures of adult mouse and rat hepatocytes for studying the metabolism of foreign compounds. Biochem. Pharmacol. 29 2117-2124. 

Nebert, D.W. and Felton, J.S. Importance of genetic factors influencing the metabolism of foreign compounds. Fed. Proc. (1976) 35 1133-1141. 

Glutathione as a sulfur nucleophile in the metabolism of foreign compounds... 

The metabolism of foreign compounds is catalyzed by enzymes, some of which are specific for the metabolism of xenobiotics. The metabolic pathways involved may be many and various but the major determinants of which transformations take place are... 

The enzymes specifically involved in the metabolism of foreign compounds are necessarily often flexible, and the substrate specificity is generally broad. However, it follows from the above two conditions that if the structure of a foreign compound is similar to a normal endogenous molecule, then the foreign compound may be a suitable substrate for an enzyme primarily involved in intermediary metabolic pathways if the enzyme is present in the exposed tissue. Thus, foreign compounds are not exclusively metabolized by specific enzymes. 

The endoplasmic reticulum is composed of a convoluted network of channels and so has a large surface area. Apart from cytochromes P-450, the endoplasmic reticulum has many enzymes and functions, besides the metabolism of foreign compounds. These include the synthesis of proteins and triglycerides and other aspects of lipid metabolism and fatty acid metabolism. Specific enzymes present on the endoplasmic reticulum include cholesterol esterase, azo reductase, glucuronosyl transferase, NADPH cytochromes P-450 reductase and NADH cytochrome b5 reductase and cytochrome b5. A FAD-containing monooxygenase is also found in the endoplasmic reticulum, and this is discussed later in this chapter. 

Amine oxidation. As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes, which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxy try pt-amine, they may be involved in the metabolism of foreign compounds. 

Metabolism of foreign compounds is not necessarily detoxication. This has already been indicated in examples and will become more apparent later in this book. This may involve activation by a phase 1 or phase 2 pathway or transport to a particular site followed by metabolism. Phase 1 reactions, particularly oxidation, can be responsible for the production of reactive intermediates such as epoxides, quinones, hydroxy la mines, and free radicals, which lead to toxicity. However, phase 2 reactions can also result in toxicity in some cases. 

But it is important to appreciate that the metabolism of foreign compounds is not completely separate from intermediary metabolism, but linked to it. Consequently, this will exert a controlling influence on the metabolism of foreign compounds. Some of the important factors controlling xenobiotic metabolism are... 

In the preceding two chapters, the disposition and metabolism of foreign compounds, as determinants of their toxic responses, were discussed. In this chapter, the influence of various chemical and biological factors on these determinants will be considered. 

As well as the sex hormones already mentioned (see above), many other hormones seem to affect the metabolism of foreign compounds and therefore may have effects on toxicity. A number of pituitary hormones may directly, as well as indirectly, affect metabolism, for example, growth hormone, follicle-stimulating hormone, adrenocorticotrophic hormone, luteinizing hormone, and prolactin. Thus, hypophysectomy in male rats results in a general decrease in metabolism, but the effects of some of the individual hormones may depend on the sex of the animal and the particular enzyme or metabolic pathway. For example, adrenocorticotrophic hormone (ACTH) administration decreases oxidative metabolism in males but increases N-demethylation in female rats. Removal of the adrenal gland reduces metabolism, such as ethylmorphine demethylation and aniline 4-hydroxylation, and this can... 

Cardiac failure may also affect metabolism by altering hepatic blood flow. However, even after heart attack without hypotension or cardiac failure, metabolism may be affected. For example, the plasma clearance of lidocaine is reduced in this situation. Other diseases such as those, which affect hormone levels hyper-or hypothyroidism, lack of or excess growth hormone, and diabetes can alter the metabolism of foreign compounds. 

The disposition or localization, and in some cases metabolism, of foreign compounds may be dependent upon the characteristics of a particular tissue or organ, which may in turn affect the toxicity. There are many examples of organotropy in toxicology, but the mechanisms underlying such organ-specific toxic effects are often unknown. 

Although first reported with the cytochrome(s) P-450 mixed function oxidases, it is now known that a number of the enzymes involved in the metabolism of foreign compounds are inducible. Thus, as well as the CYPs, NADPH cytochrome P-450 reductase, cytochrome b5, glucuronosyl transferases, epoxide hydrolases, and GSTs are also induced to various degrees. However, this discussion concentrates on the induction of the CYPs with mention of other enzymes where appropriate. 

Stress. The information available suggests that stress may increase metabolism of foreign compounds. 

Cohen GM. Pulmonary metabolism of foreign compounds Its role in metabolic activation. Environ. Health Per spec t 85 31 1990. 

The kidney is an important organ for the excretion of toxic materials and their metabolites, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The liver has as one of its functions the metabolism of foreign compounds some pathways result in detoxification and others in metabolic activation. Also, the liver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the liver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

The endoplasmic reticulum electron-transport system (NADPH-cytochrome P-450 reductase) can also generate [18]. This system, which is often responsible for the metabolism of foreign compounds, is selectively distributed in a wide variety of cell types. Its presence in hepatocytes is particularly important, since drugs are often metabolised at this site. In this system, a single electron is transferred from reduced flavin to a cytochrome P-450-substrate complex. A second electron is then transferred through this complex to O2. Production of O - may occur through auto-oxidation of the partially reduced flavin cofactor or because of uncoupling of electrons from the enzyme-substrate complex to 02 [19]. 

The general strategy of xenobiotic metabolism (the metabolism of foreign compounds) is to convert lipophilic compounds into more readily excreted polar products. The rate of this metabolism is an important determinant of the duration and intensity of the pharmacological action of drugs. Drug metabolism can result in either toxication or detoxication. While both do occur, the major metabolites of most drugs are detoxication products. 

Glucosinolinates Modify metabolism of foreign compounds and reduce yield of active carcinogens from procarcinogens... 

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