Ugt1a1

divided into two phenotypes: rapid and slow acetylators. Slow acetylators are more susceptible to semiacute and chronic toxicity of the nervous system and chemical hepatitis from these drugs and xenobiotics.

TPMT deficiency is ascribed to two major single-nucleotide polymorphisms 27 28-32

(SNPs) (at least eight have been identified) that result in low TPMT activity. TPMT deficiency is associated with life-threatening acute and delayed intolerance to immunosuppressive and antileukemic drugs (6-mercaptopurine, 6-thioguanine, azathioprine) and bleeding from cephalosporin antibiotics (moxalactam and cephamandole). In contrast, high levels of TPMT may result in failure to respond to antimetabolite therapy and leukemic relapse.

DPD deficiency occurs in 1-3% of cancer patients with solid tumors of the head, 33-38 39-43 neck, stomach, intestine, and breast. A homozygous DPD-deficient person given 5-fluorouracil (5-FU) exhibits altered 5-FU metabolism resulting in severe 5-FU toxicity. A splice site G > A mutation yields a completely nonfunctional form of DPD in sufficiently high frequency (1.8% of heterozygotes) to warrant genetic screening for the presence of this DPD variant in cancer patients before 5-FU administration.

Polymorphism of the promoter of UGT1A1, designated UGT1A1*28, is 44 45, 46

responsible for impaired glucuronidation activity. UGT1A1*28 is associated with Gilbert's syndrome, a mild nonpathogenic hyperbilirubinemia often undiagnosed disorder that occurs in up to 19% of individuals. Additionally, persons with UGT1A1*28 given irinotecan suffer severe diarrhea and leukopenia (low white blood cell counts). Irinotecan is an anticancer prodrug that is initially converted to SN-38, a highly toxic intermediate metabolite that requires glucuronidation for efficient excretion. SN-38 glucuronidation is impaired by UGT1A1*28. The polymorphism is due to an additional TA repeat in the TATA sequence of the UGT1A1 promoter [(TA)7TAA, instead of (TA)6TAA]. The frequency of UGT1A1*28 is 20%. UGT1A1*28 serves as a marker predictive of patients predisposed to irinotecan-induced gastrointestinal and bone marrow toxicity.

Fish malodor syndrome FMO3 The fish malodor syndrome is an example of a person-to-person variation in 47, 48 48

response to foods that yield trimethylamine as a breakdown product. Limited studies suggest autosomal recessive (or codominant) transmission of this trait. Its expression causes affected persons to exude the odor of rotting fish in sweat, breath, and urine. This trait is attributed to a variant form of flavin monoxygenase (FMO3). Two polymorphisms, P153L and E305X, that inactivate FMO3 appear to account for the majority of cases. Other mutations have been identified in FMO3 that determine modified and less severe forms of the condition. Affected persons can suffer devastating educational, economic, and social consequences. Management remains empirical. The usual recourse is to reduce the intake of eggs, liver, marine fish, and other trimethylamine precursors.

Multidrug resistance- ABCC2 MRP2 is one of at least nine isoforms of the multidrug resistance-related protein 53,54 49

related protein (MRP2) family of transporters.49 MPR2 functions as an ATP-dependent export pump for conjugates of lipophilic compounds with anionic residues such as glutathione and glucuronate. The genomic structure of the human MRP2 gene was determined in 1996,50 and mapped to chromosome 10q24.51,52 MPR2 is present both in basolateral and canalicular plasma membranes from normal human liver. The normal hepatic localization of MPR isoforms is altered in Dubin-Johnson syndrome, a recessive hereditary defect in hepatobiliary transport described in humans of several races and in several animal models that results in predominantly conjugated hyperbilirubinemia following its conjugation with glutathione in hepatocytes and transport to blood. The selective absence of this transport protein from the hepatocyte canalicular membrane is associated with the presence of a MRP2 isoform in the lateral plasma membrane. Several genetic variations are known to result in loss of 9 MRP2 transporter function and aberrant RNA splicing with the majority

Key References"

Polymorphic Variant Recent

Trait Gene Targeted Trait Summary discovery reference resulting in the absence of immunochemically detectable MRP2. The discovery that canalicular MRP2 is lacking in Dubin-Johnson syndrome liver is consistent with deficient unidirectional export of amphiphilic organic substrates into bile. The occurrence of the Dubin-Johnson syndrome in all races and ethnic backgrounds raises the question of whether this trait may be associated with a biological advantage under certain conditions.

Organic anion SLCO1B1 One large family of uptake transporters with members expressed in hepatocytes 60 49, 61

transporting polypep- is the OATP family of organic anion transporters. At least 11 human OATPs tide (OATP-C ) have been identified as described by the HUGO Gene Nomenclature

(OATP1B1) Committee at www.kpt.unizh.ch/oatp/. OATP-C (also designated as LST-1

and OATP2) is a major solute carrier specific to liver located at the basolateral membrane of human hepatocytes. Like other members of the organic anion transporter family, OATP-C has broad substrate selectivity, transporting various anionic compounds including bile acids, sulfate and glucuronide conjugates, estrogens, thyroid hormones, and peptides. OATP-C also has selectivity for drugs such as pravastatin, methotrexate, rifampin, and the endothelin A receptor antagonist. The genomic structure of SLCO1B1 has been determined by several groups of investigators.49 Several genetic changes in the SLCO1B1 gene have been described, three of which, N130D (338A ? G), V174A (521T ? C), and G488A (1463G ? A), may have altered function. However, reduced activity of OATP1B1 V174A protein has been observed consistently for several substrates.55,56 Genotypic analyses of subjects of European-American and African-American descent indicate that variants of OATP-C are common and racially dependent57. A novel allele of the OATP-C gene, called OATP-C*15, contains both N130D and V174A single nucleotide polymorphisms, and has a frequency in Japanese subjects of 3%.55 Individuals carrying the OATP-C*15 allele [a haplotype consisting of OATP-C*1B (Asp-130)] had increased pravastatin plasma levels as compared to individuals carrying only the OATP-C*1B allele (Asp-130-Val-174).58 Much of the functional loss associated with the OATP-C*15 haplotype is related to the V174A polymorphism. Various carriers of functionally deficient OATP-C variants exhibit reduced hepatocellular uptake of rifampin suggesting that such persons may demonstrate reduced capacity for rifampin-mediated induction of hepatic drug-metabolizing enzymes and

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