DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Drug Metabolism
Frank J. Gonzalez, Michael Coughtrie, and
Robert H. Tukey
COPING WITH EXPOSURE
TO XENOBIOTICS
Humans come into contact with thousands of foreign
chemicals, medicines, or xenobiotics (substances foreign
to the body) through intentional exposure, accidental
exposure to environmental contaminants, as well as
through diet. Fortunately, humans have developed a
means to rapidly eliminate xenobiotics so that they do
not accumulate in the tissues and cause harm. The ability
of humans to metabolize and clear drugs is a natural
process that involves the same enzymatic pathways and
transport systems that are used for normal metabolism
of dietary constituents. In fact, plants are a common
source of xenobiotics in the diet, contributing many
structurally diverse chemicals, some of which are associated
with pigment production and others of which are
toxins (called phytoallexins) that protect plants against
predators. For example, poisonous mushrooms produce
toxins that are lethal to mammals, including amanitin,
gyromitrin, orellanine, muscarine, ibotenic acid, muscimol,
psilocybin, and coprine. Animals must be able to
metabolize and eliminate such chemicals in order to consume
vegetation.
Drugs are considered xenobiotics and most are
extensively metabolized in humans. Many drugs are
derived from chemicals found in plants, some of which
have been used in Chinese herbal medicines for thousands
of years. Thus, it is not surprising that humans
also metabolize synthetic drugs by pathways that mimic
the disposition of chemicals found in the diet. This capacity
to metabolize xenobiotics, while mostly beneficial, has
made development of drugs very time consuming and
costly due in large part to:
• Inter-individual variations in the capacity of humans
to metabolize drugs
• Drug-drug interactions
• Metabolic activation of chemicals to toxic and carcinogenic
derivatives
• Species differences in expression of enzymes that
metabolize drugs, thereby limiting the use of animal
models for drug testing to predict effects in humans
A large number of diverse enzymes have evolved in animals
that apparently function only to metabolize foreign
chemicals. As will be discussed later, there are
such large differences among species in the ability to
metabolize xenobiotics, that animal models cannot be
solely relied upon to predict how humans will metabolize
a drug. Enzymes that metabolize xenobiotics have
historically been called drug-metabolizing enzymes,
although they are involved in the metabolism of many
foreign chemicals to which humans are exposed.
Thus, a more appropriate name would be xenobioticmetabolizing
enzymes. Dietary differences among
species during the course of evolution could account
for the marked species variation in the complexity of
the drug-metabolizing enzymes. Additional diversity
within these enzyme systems has also derived from the
necessity to detoxify a host of endogenous chemicals
that would otherwise prove harmful to the organism, such
as bilirubin, steroid hormones, and catecholamines.
Many of these compounds are detoxified by the same or
closely related xenobiotic-metabolizing enzymes.
Xenobiotics to which humans are exposed
come from sources that include environmental
pollution, food additives, cosmetic products, agrochemicals,
processed foods, and drugs. In general, most
xenobiotics are lipophilic chemicals that, in the absence
of metabolism, would not be efficiently eliminated, and
thus would accumulate in the body, potentially resulting
in toxicity. With very few exceptions, xenobiotics are
subjected to one or multiple enzymatic pathways that