Factors Affecting Metabolism of Xenobiotics

Many factors affect the metabolism of xenobiotics. These include 

The developing fetus and neonate have little or no ability to metabolize xenobiotics. Though the fetus is protected by its mother in utero, it is particularly vulnerable to assault by xenobiotics. The effects of xenobiotics on the developing fetus are discussed in some detail in subsequent chapters. 

The ability to metabolize xenobiotics develops rapidly after birth, peaks in early adulthood, and ebbs with age. The very young and the aged are impacted to a far greater degree by absorbed chemicals than young adults. 

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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. 

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. 

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. 

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. 

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. 

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