Harpers

630 / CHAPTER 53This reaction helps transfer certain amino acids acrossthe plasma membrane, the amino acid being subsequentlyhydrolyzed from its complex with GSH andthe GSH being resynthesized from cysteinylglycine.The enzyme catalyzing the above reaction is -glutamyltransferase(GGT). It is present in the plasmamembrane of renal tubular cells and bile ductule cells,and in the endoplasmic reticulum of hepatocytes. Theenzyme has diagnostic value because it is released intothe blood from hepatic cells in various hepatobiliarydiseases.D. OTHER REACTIONSThe two most important other reactions are acetylationand methylation.1. Acetylation—Acetylation is represented byX + Acetyl-CoA → Acetyl-X + CoAwhere X represents a xenobiotic. As for other acetylationreactions, acetyl-CoA (active acetate) is the acetyldonor. These reactions are catalyzed by acetyltransferasespresent in the cytosol of various tissues, particularlyliver. The drug isoniazid, used in the treatment oftuberculosis, is subject to acetylation. Polymorphictypes of acetyltransferases exist, resulting in individualswho are classified as slow or fast acetylators, and influencethe rate of clearance of drugs such as isoniazidfrom blood. Slow acetylators are more subject to certaintoxic effects of isoniazid because the drug persistslonger in these individuals.2. Methylation—A few xenobiotics are subject tomethylation by methyltransferases, employing S-adenosylmethionine(Figure 30–17) as the methyl donor.THE ACTIVITIES OF XENOBIOTIC-METABOLIZING ENZYMES AREAFFECTED BY AGE, SEX,& OTHER FACTORSVarious factors affect the activities of the enzymes metabolizingxenobiotics. The activities of these enzymesmay differ substantially among species. Thus, for example,the possible toxicity or carcinogenicity of xenobioticscannot be extrapolated freely from one species toanother. There are significant differences in enzyme activitiesamong individuals, many of which appear to bedue to genetic factors. The activities of some of theseenzymes vary according to age and sex.Intake of various xenobiotics such as phenobarbital,PCBs, or certain hydrocarbons can cause enzyme induction.It is thus important to know whether or notan individual has been exposed to these inducing agentsin evaluating biochemical responses to xenobiotics.Metabolites of certain xenobiotics can inhibit or stimulatethe activities of xenobiotic-metabolizing enzymes.Again, this can affect the doses of certain drugs that areadministered to patients. Various diseases (eg, cirrhosisof the liver) can affect the activities of drug-metabolizingenzymes, sometimes necessitating adjustment ofdosages of various drugs for patients with these disorders.RESPONSES TO XENOBIOTICSINCLUDE PHARMACOLOGIC,TOXIC, IMMUNOLOGIC,& CARCINOGENIC EFFECTSXenobiotics are metabolized in the body by the reactionsdescribed above. When the xenobiotic is a drug,phase 1 reactions may produce its active form or maydiminish or terminate its action if it is pharmacologicallyactive in the body without prior metabolism. Thediverse effects produced by drugs comprise the area ofstudy of pharmacology; here it is important to appreciatethat drugs act primarily through biochemical mechanisms.Table 53–2 summarizes four important reactionsto drugs that reflect genetically determineddifferences in enzyme and protein structure among individuals—partof the field of study known as pharmacogenetics(see below).Table 53–2. Some important drug reactions dueto mutant or polymorphic forms of enzymes orproteins. 1Enzyme or ProteinAffectedReaction or ConsequenceGlucose-6-phosphate Hemolytic anemia following indehydrogenase(G6PD) gestion of drugs such as prim-[mutations] (MIM 305900) aquineCa 2+ release channel (ryan- Malignant hyperthermia (MIModine receptor) in the 145600) following administrasarcoplasmicreticulum tion of certain anesthetics (eg,[mutations] (MIM 180901) halothane)CYP2D6 [polymorphisms](MIM 124030)CYP2A6 [polymorphisms](MIM 122720)Slow metabolism of certaindrugs (eg, debrisoquin), resultingin their accumulationImpaired metabolism of nicotine,resulting in protectionagainst becoming a tobaccodependentsmoker1 G6PD deficiency is discussed in Chapters 20 and 52 and malignanthyperthermia in Chapter 49. At least one gene other thanthat encoding the ryanodine receptor is involved in certain casesof malignant hypertension. Many other examples of drug reactionsbased on polymorphism or mutation are available.