Xenobiotics, metabolism factors affecting

Various factors affect the activities of the enzymes metabolizing xenobiotics. The activities of these enzymes may differ substantially among species. Thus, for example, the possible toxicity or carcinogenicity of xenobiotics cannot be extrapolated freely from one species to another. There are significant differences in enzyme activities among individuals, many of which appear to be due to genetic factors. The activities of some of these enzymes vary according to age and sex. 

There are many factors, both chemical and biological, which affect the disposition of xenobiotics. Chemical factors include size and structure, pKa, chirality, and lipophilicity. Biological factors include species, sex and strain, genetic factors, hormonal influences, disease and pathological conditions, age, stress, diet, dose, enzyme induction and inhibition, and tissue and organ specificity. All of these factors can affect the toxicity of a chemical by changing its disposition, especially its metabolism. 

Hodgson E. Chemical and environmental factors affecting metabolism of xenobiotics. In Hodgson E, Levi PE, eds. Introduction to Biochemical Toxicology. 2nd ed. Connecticut Appleton-Lange, 1994. Jakoby WE, ed. Enzymatic Basis of Detoxication. New York Academic Press, 1980. 

Ronis MJJ, Cunny HC. Physiological (endogenous) factors affecting Xenobiotic Metabolism In Hodgson E, Smart RC, eds. Introduction to Biochemical Toxicology. 3rd ed. New York Wiley Interscience, 2001. 

Because endogenous factors also affect the enzymes of xenobiotic metabolism, the toxic sequelae to be expected from a particular toxicant will vary with developmental stage, nutritional statue, health or physiological status, stress or environment. 

Ronis, M. J. J., and H. C. Cunny. Physiological factors affecting xenobiotic metabolism. In Introduction to Biochemical Toxicology, 3rd ed., E. Hodgson, and R. C. Smart, eds. New York Wiley, 2001. 

Factors affecting metabolism and disposition of drugs or xenobiotics in vivo have been amply described elsewhere (Timbrell, 1991). They may be divided into biological factors and molecular factors. 

Many factors affect the metabolism of xenobiotics. These include... 

TABLE 32.7 Biological Factors Affecting Xenobiotic Metabolism. ... 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

It is widely agreed that the factors that affect the structure and function of the gastrointestinal tract are manifold, especially those parts of the gut involved in absorption and first-pass xenobiotic metabolism. The most significant of these are described below. 

Age, Sex, Inducers and Inhibitors of Metabolism. The ability of an organ to activate a specific toxin is one explanation of organ-selective toxicity. Factors such as age, sex, circadian rhythms, nutritional status, and exposure to chemicals are known to affect xenobiotic metabolizing enzymes, and therefore might affect organ-specific toxicity of metabolically activated toxins. Several of these factors have striking effects on the organ-specific toxicity produced by IPO. 

In vitro Effects. In vitro measurement of the effect of one xenobiotic on the metabolism of another is by far the most common type of investigation of interactions involving inhibition. Although it is the most useful method for the study of inhibitory mechanisms, particularly when purified enzymes are used, it is of limited utility in assessing the toxicological implications for the intact animal. The principal reason for this is that in vitro measurement does not assess the effects of factors that affect absorption, distribution, and prior metabolism, all of which occur before the inhibitory event under consideration. 

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