The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

The human CYP2A6 enzyme metabolizes certain drugs and pre-carcinogens and appears to be the most important enzyme for nicotine metabolism. At present, more than 10 different allelic variants are known that cause abolished or decreased enzyme activity. Genetic polymorphism in this gene might be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. We have identified a new CYP2A6 allele (CYP2A6*12) which carries an unequal crossover between the CYP2A6 and CYP2A7 genes in intron 2. This results in a hybrid allele where the 5' regulatory region and exons 1-2 are of CYP2A7 origin and exons 3-9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6(*)1 allele. Phenotyping with the CYP2A6 substrate coumarin indicates that it causes reduced CYP2A6 activity in'vivo. Furthermore, when expressed in mammalian COS-1 cells, the enzyme variant catalyzed 7-hydroxylation of coumarin at a rate approximately 60% of that of the wild-type enzyme. The CYP2A6(*)12 allele was present at an allele frequency of 2.2% among Spaniards, but was absent in Chinese.

Abstract. GLUTI, the erythrocyte glucose transporter, and GLUT4, the adipose/muscle transporter, were each expressed in NIH-3T3 cells by retrovirus-mediated gene transfer. In fibroblasts overexpressing GLUT1, basal as well as insulin-stimulated deoxyglucose uptake was increased. Expression of GLUT4 was without affect on either basal or hormone stimulated hexose uptake. Localization of each of the transporters by indirect immunofluorescence revealed that, whereas GLUTI was found primarily on the cell surface, GLUT4 was directed to vesicles in a perinuclear distribution and throughout the cytoplasm. The GLUT4-containing compartment represented neither Golgi complex nor lysosomes, as evidenced by the failure of 1gp110 or Golgi mannosidase to co-localize. However, ONE of the best-characterized actions of the anabolic hormone insulin is its ability to rapidly and reversibly increase the rate of glucose metabolism in pe ripheral target tissues (8). The flux of sugars across the plasma membrane ofmammaliancells is catalyzed by a class of integral membrane glycoproteins, the facilitated hexose transporters . It is this process which is the primary site of action by which insulin modulates glucose uptake . A number of years ago, it became clear that in the basal state a substantial number of glucose transporters in adipose tissue and probably muscle reside within the cell, where they are inactive presumably solely because of their inaccessibility to extracellular sugars (36) . Shortly after exposure to insulin, the adipose cell redistributes its glucose transporters such that a greater number are located on the cell surface and contribute to the influx of hexoses. Whereas it remains unclear as to whether the "translocation" model explains all of the increase in hexose uptake in response to hormone, redistribution certainly occurs and is important to the overall augmented glucose flux. Therefore, a major part of understanding the mechanism by which insulin regulates hexose metabolism involves characterizing the pathways of subcellular trafficking of glucose transport proteins .Recently, the existence of a gene family encoding related glucose transport proteins has been firmly established (4) . The two isoforms relevant to the experiments discussed be- there was substantial overlap between the distribution of GLUT4 and the transferrin receptor, and some colocalization of the transporter isoform with the mannose-6-phosphate receptor. In addition, when FITCwheat germ agglutinin bound to the cell surface was allowed to internalize at 37°C, it concentrated in vesicular structures coincident with GLUT4 immunoreactivity.These data establish that GLUTI and GLUT4 contain within their amino acid sequences information which dictates targeting to distinct cellular compartments. Moreover, GLUT4 can be recognized by those cellular factors which direct membrane proteins to the endosomal pathway. low are GLUTI and GLUT4. cDNAs encoding the former were originally cloned from human hepatoma and rat brain, and probably also code for the wel...

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