Weber WW


Full name : Wendell W

First name : Wendell W

Mail : Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632

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Country : USA

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References (8)

Title : The promise of epigenetics in personalized medicine - Weber_2010_Mol.Interv_10_363
Author(s) : Weber WW
Ref : Mol Interv , 10 :363 , 2010
Abstract : Numerous preclinical and clinical trials, with older as well as some newer drugs, have demonstrated the targeting of aberrant epigenetic marks to be a viable means of preventing and treating certain human disorders, including myelodysplastic and leukemic syndromes and various hemoglobinopathies. These findings are encouraging, and although the risks associated with such therapy are largely unknown, precise maps of epigenetic marks are becoming increasingly available through advancements in sequencing protocols that combine chromatin immunoprecipitation and gene expression analyses. Indeed, progress in understanding gene regulation at promoter regions and chromatin organization in health and disease has been substantial. New insights into the proteins that are targeted by therapeutic agents that alter epigenetic programs may provide important inroads into personalized medicine.
ESTHER : Weber_2010_Mol.Interv_10_363
PubMedSearch : Weber_2010_Mol.Interv_10_363
PubMedID: 21263162

Title : Pharmacogenetics: from description to prediction - Weber_2008_Clin.Lab.Med_28_499
Author(s) : Weber WW
Ref : Clin Lab Med , 28 :499 , 2008
Abstract : Many of the complexities of human drug response are sufficiently well understood to transform the field of pharmacogenetics from a descriptive science to a predictive science. Clinical application of these markers is currently limited by lack of knowledge about the effects of modifying genes, about their prevalence and risk contribution in different ethnogeographic populations, and by fragmentary information about how genetic factors interact with physiologic or pathologic and other environmental factors. Nevertheless, progress has been notable, as exemplified in the identification of genetic markers predictive of pharmacokinetic variation, and in markers predictive of outcome and therapeutic benefit in the treatment of cancer.
ESTHER : Weber_2008_Clin.Lab.Med_28_499
PubMedSearch : Weber_2008_Clin.Lab.Med_28_499
PubMedID: 19059058

Title : Pharmacogenetics of the arylamine N-acetyltransferases: a symposium in honor of Wendell W. Weber - Hein_2000_Drug.Metab.Dispos_28_1425
Author(s) : Hein DW , McQueen CA , Grant DM , Goodfellow GH , Kadlubar FF , Weber WW
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 28 :1425 , 2000
Abstract : This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics presented at the joint meeting of the American Society for Biochemistry and Molecular Biology and the American Society for Pharmacology and Experimental Therapeutics, June 4-8, Boston, Massachusetts. The presentations focused on the pharmacogenetics of the NAT1 and NAT2 arylamine N-acetyltransferases, including developmental regulation, structure-function relationships, and their possible role in susceptibility to breast, colon, and pancreatic cancers. The symposium honored Wendell W. Weber for over 35 years of leadership and scientific advancement in pharmacogenetics and was highlighted by his overview of the historical development of the field.
ESTHER : Hein_2000_Drug.Metab.Dispos_28_1425
PubMedSearch : Hein_2000_Drug.Metab.Dispos_28_1425
PubMedID: 11095579

Title : Populations and genetic polymorphisms - Weber_1999_Mol.Diagn_4_299
Author(s) : Weber WW
Ref : Mol Diagn , 4 :299 , 1999
Abstract : BACKGROUND: Population frequencies of many polymorphic genes of pharmacogenetic interest depend on race or ethnic specificity. Association of these genes with person-to-person differences in drug effectiveness (hypersensitivity or resistance) and drug toxicity may also depend on the racial or ethnic characteristics of a population. Information about ethnic specificity is an integral part of pharmacogenetics because it can suggest a starting point for further study of these traits, tailoring drug therapy to the individual patient, and rational development and clinical trials of new drugs. Ethnic specificities of several medically important metabolic traits serve to illustrate these ideas. Among the traits considered is primaquine sensitivity, a sex-linked trait attributed to glucose-6-phosphate dehydrogenase deficiency that mainly affects males among African, Mediterranean, and Oriental people. Additional examples include the remarkable sensitivity of the Japanese to alcohol (ethanol) compared with whites; the ethnic specificity of the cytochrome P-450 enzyme CYP2D6* (debrisoquine/sparteine) polymorphism that results in poor, extensive, and ultrarapid metabolizers of at least 30 drugs; the CYP2C19* (mephenytoin) polymorphism that accounts for variable metabolism of proguanil, omeprazole, and certain barbiturates; and the polymorphic (NAT2*) acetylation of hydrazine and aromatic amine drugs, such as isoniazid, hydralazine, and sulfasalazine.
ESTHER : Weber_1999_Mol.Diagn_4_299
PubMedSearch : Weber_1999_Mol.Diagn_4_299
PubMedID: 10671640

Title : Influence of heredity on human sensitivity to environmental chemicals - Weber_1995_Environ.Mol.Mutagen_25 Suppl 26_102
Author(s) : Weber WW
Ref : Environmental & Molecular Mutagenesis , 25 Suppl 26 :102 , 1995
Abstract : Hereditary peculiarities in individual responses to environmental chemicals are a common occurrence in human populations. Genetic variation in glutathione S-transferase, CYP1A2, N-acetyltransferase, and paraoxonase exemplify the relationship of metabolic variation to individual susceptibility to cancer and other toxicants of environmental origin. Heritable receptor protein variants, a subset of proteins of enormous pharmacogenetic potential that have not thus far been extensively explored from the pharmacogenetic standpoint, are also considered. Examples of interest that are considered include receptor variants associated with retinoic acid resistance in acute promyelocytic leukemia, with paradoxical responses to antiandrogens in prostate cancer, and with retinitis pigmentosa. Additional heritable protein variants of pharmacogenetic interest that result in antibiotic-induced deafness, glucocorticoid-remediable aldosteronism and hypertension, the long-QT syndrome, and beryllium-induced lung disease are also discussed. These traits demonstrate how knowledge of the molecular basis and mechanism of the variant response may contribute to its prevention in sensitive persons as well as to improved therapy for genetically conditioned disorders that arise from environmental chemicals.
ESTHER : Weber_1995_Environ.Mol.Mutagen_25 Suppl 26_102
PubMedSearch : Weber_1995_Environ.Mol.Mutagen_25 Suppl 26_102
PubMedID: 7789356

Title : Molecular genetic basis of rapid and slow acetylation in mice - Martell_1991_Mol.Pharmacol_40_218
Author(s) : Martell KJ , Vatsis KP , Weber WW
Ref : Molecular Pharmacology , 40 :218 , 1991
Abstract : The molecular genetic basis of N-acetylation polymorphism has been investigated in inbred mouse models of the human acetylation polymorphism. Two genomic clones, Nat1 and Nat2, were isolated from a C57BL/6J (B6) mouse (rapid acetylator) genomic library. The Nat1 and Nat2 genes both have intronless coding regions of 870 nucleotides and display greater than 47% deduced amino acid similarity with human, rabbit, and chicken N-acetyltransferases. Amplification of Nat1 and Nat2 from A/J (A) mouse (slow acetylator) genomic DNA by the polymerase chain reaction and subsequent sequencing revealed that Nat1 was identical in B6 and A mice, whereas Nat2 contained a single nucleotide change from adenine in B6 to thymine in A mice. This nucleotide substitution changes the deduced amino acid at position 99 from asparagine in B6 to isoleucine in A mice. Hydropathy analysis revealed that this amino acid change alters the hydropathy of the flanking peptide segment in NAT2 from hydrophilic in the B6 mouse to hydrophobic in the A mouse. The amino acid change occurs in a region of the gene where no polymorphism has yet been reported in human or rabbit NAT2 and may represent an important structural domain for N-acetyltransferase activity. Nat1 and Nat2 have the same 5' to 3' orientation in the B6 mouse; the two genes are separated by approximately 9 kilobases, with Nat1 located 5' of Nat2.
ESTHER : Martell_1991_Mol.Pharmacol_40_218
PubMedSearch : Martell_1991_Mol.Pharmacol_40_218
PubMedID: 1875909

Title : Acetylation - Weber_1990_Birth.Defects.Orig.Artic.Ser_26_43
Author(s) : Weber WW
Ref : Birth Defects Orig Artic Ser , 26 :43 , 1990
Abstract : The human acetylation polymorphism has been known for more than three decades since its discovery during the metabolic investigation of the antituberculous hydrazine drug, isoniazid. The trait was originally known as the "isoniazid acetylation polymorphism" but is now usually abbreviated to the "acetylation polymorphism" because the acetylation of numerous hydrazine and arylamine drugs and other chemicals are subject to this trait. A. Individuals phenotype as "slow" acetylators, homozygous for the slow acetylator gene, or "rapid" acetylators either heterozygous or homozygous for the rapid acetylator gene. Differences in individual acetylating capacity are ascribed to differences in the activities of the arylamine acetylating enzymes (isozymic N-acetyltransferase variants) of the liver, intestinal mucosa and certain other tissues. The chromosomal locus of the human gene has not been determined, but linkage analysis in mice indicates that the N-acetyltransferase gene is closely linked to Esterase-1 on mouse chromosome 8. Recommendation: 1) That the chromosomal locus of the human acetylator gene(s) be determined. B. The acetylator phenotype is a lifelong, stable characteristic of the individual that can be determined by procedures using any of several test agents (eg, caffeine, isoniazid, sulfamethazine, sulfapyridine). All suitable test agents discriminate rapid and slow acetylator phenotypes, whereas caffeine enables homozygous and heterozygous rapid acetylators to be discriminated from each other and from slow acetylators. These procedures can be used with confidence to determine the acetylator status of healthy adults and children but caution is necessary in interpreting this information for infants, in altered physiologic states and in the presence of certain diseases and environmental substances. Recommendations: 1) That investigators should strongly consider the use of the caffeine test for acetylator phenotype determination in human epidemiologic studies of acetylation because of its advantages over other test agents that are available. 2) That efforts to determine the structure of the acetylator genes responsible for the human acetylator polymorphism, and to determine the genes responsible for the hereditary acetylator polymorphisms in animal models for the human trait be continued apace with efforts on the human system. 3) That an improved test to determine the acetylator status utilizing that information and current molecular biology approaches and techniques applied to tissues that are readily available in human subjects (eg, leukocytes) be developed at a high priority. C. The hereditary acetylator status of individuals provides valuable information about their therapeutic, pharmacologic and toxicologic responses and is a prognosticator of unusual susceptibility to toxicity from drugs widely used for the treatment of diverse diseases.
ESTHER : Weber_1990_Birth.Defects.Orig.Artic.Ser_26_43
PubMedSearch : Weber_1990_Birth.Defects.Orig.Artic.Ser_26_43
PubMedID: 2224079

Title : Linkage of Nat and Es-1 in the mouse and development of strains congenic for N-acetyltransferase - Mattano_1988_J.Hered_79_430
Author(s) : Mattano SS , Erickson RP , Nesbitt MN , Weber WW
Ref : Journal of Heredity , 79 :430 , 1988
Abstract : The human polymorphism in the hepatic enzyme N-acetyltransferase (NAT) affects the rate at which individuals acetylate, and in many cases detoxify, aromatic amine and hydrazine drugs and xenobiotics. Differences in NAT activity are known to affect individual susceptibility to drug toxicities and are thought to play a part in some spontaneous disorders. A mouse model for the human acetylation polymorphism has been previously characterized and involves the A/J (slow acetylator) and C57BL/6J (rapid acetylator) inbred strains. Strain distribution analysis of 40 A x B and B x A recombinant inbred (RI) strains indicated linkage between the N-acetyltransferase gene (Nat) and the esterase 1 (Es-1) gene, located on mouse chromosome 8. A double backcross involving 107 animals confirmed the recombination frequency between Nat and Es-1 to be 12 +/- 3% (mean +/- SE). The information obtained in the backcross and RI studies was combined, yielding a 13 +/- 2.8% (mean +/- SD) recombination frequency. The Es-1 genotype was determined in our newly developed congenic strains A.B6-Natr and B6.A-Nats. The B6.A-Nats strain has the Es-1 genotype of its inbred partner, the B6 strain, and the A.B6-Natr strain has the Es-1 genotype of the donor strain. These congenic strains will be important in determining the role of the NAT genotype in susceptibility to arylamine-induced cancer and other disorders.
ESTHER : Mattano_1988_J.Hered_79_430
PubMedSearch : Mattano_1988_J.Hered_79_430
PubMedID: 3209851