Pharmacogenetics

Propping, Peter

doi:10.1007/3-540-08907-1_4

Cited by 25 publications

(6 citation statements)

References 123 publications

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“…Ecogenetics is understood to be a genetic predisposition for an individual reaction to environmental factors (Brewer 1971, Goedde 1972, Propping 1978, 1980, Kalow 1982, Kalow et al 1986). Ecogenetic reactions are found in all groups of living organisms.…”

Section: Introductionmentioning

confidence: 99%

Ecogenetics

Mallinckrodt¹

2004

Elements and Their Compounds in the Environment

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Section: Introductionmentioning

confidence: 99%

Ecogenetics

Mallinckrodt¹

2004

Elements and Their Compounds in the Environment

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“…These factors include age, sex, genetic composition, nutritional status, and preexisting disease conditions (1)(2)(3)(4)(5). These factors include age, sex, genetic composition, nutritional status, and preexisting disease conditions (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Comparative Biology of Test Species

Calabrese¹

1988

Environmental Health Perspectives

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JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, -glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated. variation among humans in response to toxic agents. This information is necessary to establish the biological basis of the uncertainty (safety) factor of 10 currently recommended for within human species variation by the National Academy of Sciences (6) and used by the U.S. Environmental Protection Agency (8) in establishing acceptable exposure standards for noncarcinogens. Unfortunately, the recommended use of such an uncertainty factor by the National Research Council (6) has not been accompanied by supportive documentation. The numerous problems related to the heterogeneity of human responses to carcinogenic agents becomes apparent with the understanding that current procedures for quantitative risk assessment apply biomathematical models to bioassay data. This procedure assumes that the human distribution of sensitivities will be described by the response of inbred animal models. Current approaches for predicting human cancer risks from animal studies do not consider human heterogeneity. Variation in Response to Selected XenobioticsThe following examples will examine the range of human responses with respect to the degree of variation in xenobiotic metabolism a...

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“…[See Goedde et al (1967), Kalow (1962), Motulsky (t 964), Price-Evans (1968, 1977, Propping (1978), Sjoqvist et al (1980), Szonidy (1973), Vesell (1975Vesell ( , 1977Vesell ( , 1979; and WHO Technical Report (1973). ]…”

mentioning

confidence: 99%

Defective Oxidation of Drugs

Eichelbaum¹

1982

Clinical Pharmacokinetics

168

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Until quite recently. pharmacogenetic polymorphisms in oxidative drug metabolism were considered rare. However during the last years several monogenically determined poly of oxidative reactions in drug metabolism involving benzylic hydroxylation of debrisoquine, N-oxidation qf sparteine, C-hydroxylation qf tolbutamide, O-de-ethylation of phenacetin, phydroxylation qf phenytoin and mephenytoin and N-glucosidation of amylobarbitone (amobarbital) have been discovered. The incidence qf these various pharmacogenetic conditions varies between 2 and 9 % of the population. Among these conditions the best studied examples are the polymorphic oxidation qf debrisoquine and sparteine.

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Pharmacogenetics

Cited by 25 publications

References 123 publications

Ecogenetics

Ecogenetics

Comparative Biology of Test Species

Defective Oxidation of Drugs

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