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VOL. 73 (1), 5-26, 2007 IN VITRO INVESTIGATION OF DRUG METABOLISM AND TOXICITY...

VARIABILITY OF DRUG METABOLIC CAPABILITY
IN HUMANS

Variability of drug metabolism rates is a consistent observation
in human populations. Considerable differences can be observed
among «extreme» individuals. Progressive advances in the knowledge
of metabolic routes and enzymes responsible for drug
biotransformation have contributed to understanding the great
metabolic variations existing in human beings. Phenotypic and
genotypic differences in the expression of the enzymes involved in
drug metabolism are the main causes of this variability. It is well
documented that P450 enzymes are polymorphically expressed (59,
64, 65). Mutations of P450 genes result in allelic variants causing
defective, qualitatively altered, diminished or enhanced rates of drug
metabolism. As a consequence, polymorphisms can lead to
qualitative and/or quantitative alterations in the metabolism of drugs
and could be responsible for the development of a number of
unexpected adverse drug reactions and host-specific susceptibility to
drugs or other chemicals. An association between polymorphisms
and increased toxicity risk or cancer has been reported (66). Among
P450 polymorphisms, those affecting CYP2C9, CYP2C19 and,
particularly CYP2D6, have the highest impact on drug metabolism
(67, 68). At present, a high number of CYP2D6 allelic variants (ca.
50) have been identified, some resulting in appreciable changes in
enzyme function. In contrast, CYP1A1, CYP2E1 and CYP3A4 genes
are relatively well conserved and only a few, if any, rare variants
yielding changes in catalytic enzyme activity have been found (65).

Interindividual differences in catalytic activities cannot be
exclusively attributed to genetic polymorphisms, and non-genetic
factors should be considered as a leading cause of the great
variability existing in drug metabolism rates. Age, gender, hormonal
status, liver pathologies and drug intake can influence the P450
function. CYP3A4, the most abundant P450 in the human liver,
constitutes a good example of phenotypic variability. Variations in
CYP3A4 activity cannot be explained by the genotype as only rare
allelic variants with no major functional effects have been identified
(69). CYP3A4 variability is probably a direct consequence of the
modulation of gene expression by environmental factors. The enzyme

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