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ABBREVIATIONS

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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 and clear ...

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