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Abbreviations
ADR: adverse drug reaction
AUC: area under the plasma concentration–time curve
AZA: azathioprine
CAR: constitutive androstane receptor
CES2: carboxylesterase 2
COMT: catechol-O-methyltransferase
CPT-11: irinotecan
CYP: cytochrome P450
DPYD: dihydropyrimidine dehydrogenase
EH: epoxide hydrolase
FMO: flavin-containing monooxygenase
GI: gastrointestinal
GSH and GSSG: reduced and oxidized glutathione
GST: glutathione-S-transferase
HGPRT: hypoxanthine guanine phosphoribosyl transferase
HIF: hypoxia-inducible factor
HIV: human immunodeficiency virus
HNMT: histamine N-methyltransferase
HPPH: 5-(-4-hydroxyphenyl)-5-phenylhydantoin
INH: isonicotinic acid hydrazide (isoniazid)
MAO: monoamine oxidase
MAPK: mitogen-activated protein kinase
mEH: microsomal epoxide hydrolase
6-MP: 6-mercaptopurine
MRP: multidrug resistance protein
MT: methyltransferase
NADPH: nicotinamide adenine dinucleotide phosphate
NAPQI: N-acetyl-p-benzoquinone imine
NAT: N-acetyltransferase
NNMT: nicotinamide N-methyltransferase
PAPS: 3′-phosphoadenosine-5′-phosphosulfate
Per: Period
Pgp: P-glycoprotein
PNMT: phenylethanolamine N-methyltransferase
POMT: phenol-O-methyltransferase
PPAR: peroxisome proliferator–activated receptor
PXR: pregnane X receptor
RXR: retinoid X receptor
SAM: S-adenosyl-methionine
sEH: soluble epoxide hydrolase
SULT: sulfotransferase
TBP: TATA box–binding protein
6-TGN: 6-thioguanine nucleotide
TMA: trimethylamine
TPMT: thiopurine methyltransferase
TPT: thiol methyltransferase
UDP-GA: uridine diphosphate–glucuronic acid
UGT: uridine diphosphate–glucuronosyltransferase
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COPING WITH XENOBIOTICS
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Humans come into contact with thousands of foreign chemicals or xenobiotics (substances foreign to the body) through diet and exposure to environmental contaminants. Fortunately, humans have developed a means to rapidly eliminate xenobiotics so that they do not accumulate in the tissues and cause harm. Plants are a common source of dietary xenobiotics, providing many structurally diverse chemicals, some of which are associated with pigment production and others that are actually toxins (called phytoalexins) that protect plants against predators. Poisonous mushrooms are a common example: They have many 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 to consume vegetation. While humans can now choose their dietary sources, a typical animal does not have this luxury and as a result is subject to its environment and the vegetation that exists in that environment. Thus, the ability to metabolize unusual chemicals in plants and other food sources is critical for adaptation to a changing environment and ultimately the survival of animals.
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Enzymes that metabolize xenobiotics have historically been called drug-metabolizing enzymes; however, these enzymes are involved in the metabolism of many foreign chemicals to which humans are exposed and are more appropriately called xenobiotic-metabolizing enzymes. Myriad diverse enzymes have evolved in animals to metabolize foreign chemicals. Dietary differences among species during the course of evolution could account for the marked species variation in the complexity of the xenobiotic-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 endogenous biochemicals are detoxified by the same or closely related xenobiotic-metabolizing enzymes.
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Drugs are xenobiotics, and the capacity to metabolize ...