the human body. The physicochemical properties of a large number of small
molecule drugs are in a range where such enzymes are able to bind them as substrates
at their active site and to convert them into metabolites with generally enhanced
susceptibility to excretion and thus irreversible removal from the organism. As
described in more detail in chapter “General Introduction on Pharmaceuticals”, the
chemical structures of most orally dosed pharmaceuticals are optimized for high
metabolic stability with the objective of reducing dose size and dosing frequency.
Nonetheless, enzyme-mediated biotransformations eventually constitute the principal clearance mechanism. In view of the exceptional role of drug-metabolizing
enzymes (DME) in the compound optimization strategies applied in rational drug
design, the catalyzed reactions, their tissue-specific expression and subcellular
localization, their substrate selectivity, and their inducibility and polymorphism
have been characterized in a very comprehensive fashion.
Although all organs and tissues in the human body exhibit DME activity to some
degree, the most important site of drug metabolism is the liver followed by notable
contributions from enzymes expressed in the intestine, the kidneys, and plasma. The
fundamental importance of hepatic DMEs arises from the anatomical position of the
liver acting as the port of entry into systemic circulation of organic compounds
previously absorbed in the intestinal tract and delivered through the portal vein to the
liver (see chapter “General Introduction on Pharmaceuticals”).
At the highest level, human DMEs are classified into one of two categories: phase
I enzymes catalyze oxidative, reductive, and hydrolytic reactions, whereas phase II
enzymes mediate the transfer of larger moieties from a cofactor to the substrate
thereby generating conjugates. In most instances, the increase in polarity induced by
phase I reactions is modest and may produce metabolites being sufficiently permeable to passively diffuse from the liver back into the blood stream. Phase II
metabolites, in contrast, are usually of substantially lower lipophilic nature than
their parent compound. Despite the detrimental effect of reduced lipophilicity on
passive membrane permeability, transmembrane proteins located on the apical side
of the hepatocyte help transport conjugates against a concentration gradient into bile
and thereby facilitate excretion. It is not uncommon to observe metabolites in human
wastes, originating from biliary or renal excretion, that have been formed by a
sequence or combination of phase I and phase II reactions.
2.1 Phase I Reactions
Among the phase I enzymes, the superfamily of the highly versatile monooxygenase
cytochrome P450 (CYP) is the single most prominent one [4, 5]. CYP enzymes are
divided into families based on their amino acid homology; members of the same
family (indicated by a letter) share 40% homology, while those of the subfamily
(indicated by a number) overlap by at least 55% of their amino acid sequence. Of the
CYPs recognizing and transforming synthetic drug molecules, the human isoforms
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are the most important
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
225
molecule drugs are in a range where such enzymes are able to bind them as substrates
at their active site and to convert them into metabolites with generally enhanced
susceptibility to excretion and thus irreversible removal from the organism. As
described in more detail in chapter “General Introduction on Pharmaceuticals”, the
chemical structures of most orally dosed pharmaceuticals are optimized for high
metabolic stability with the objective of reducing dose size and dosing frequency.
Nonetheless, enzyme-mediated biotransformations eventually constitute the principal clearance mechanism. In view of the exceptional role of drug-metabolizing
enzymes (DME) in the compound optimization strategies applied in rational drug
design, the catalyzed reactions, their tissue-specific expression and subcellular
localization, their substrate selectivity, and their inducibility and polymorphism
have been characterized in a very comprehensive fashion.
Although all organs and tissues in the human body exhibit DME activity to some
degree, the most important site of drug metabolism is the liver followed by notable
contributions from enzymes expressed in the intestine, the kidneys, and plasma. The
fundamental importance of hepatic DMEs arises from the anatomical position of the
liver acting as the port of entry into systemic circulation of organic compounds
previously absorbed in the intestinal tract and delivered through the portal vein to the
liver (see chapter “General Introduction on Pharmaceuticals”).
At the highest level, human DMEs are classified into one of two categories: phase
I enzymes catalyze oxidative, reductive, and hydrolytic reactions, whereas phase II
enzymes mediate the transfer of larger moieties from a cofactor to the substrate
thereby generating conjugates. In most instances, the increase in polarity induced by
phase I reactions is modest and may produce metabolites being sufficiently permeable to passively diffuse from the liver back into the blood stream. Phase II
metabolites, in contrast, are usually of substantially lower lipophilic nature than
their parent compound. Despite the detrimental effect of reduced lipophilicity on
passive membrane permeability, transmembrane proteins located on the apical side
of the hepatocyte help transport conjugates against a concentration gradient into bile
and thereby facilitate excretion. It is not uncommon to observe metabolites in human
wastes, originating from biliary or renal excretion, that have been formed by a
sequence or combination of phase I and phase II reactions.
2.1 Phase I Reactions
Among the phase I enzymes, the superfamily of the highly versatile monooxygenase
cytochrome P450 (CYP) is the single most prominent one [4, 5]. CYP enzymes are
divided into families based on their amino acid homology; members of the same
family (indicated by a letter) share 40% homology, while those of the subfamily
(indicated by a number) overlap by at least 55% of their amino acid sequence. Of the
CYPs recognizing and transforming synthetic drug molecules, the human isoforms
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are the most important
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
225