Comparison of TCDD and PCB CYP1A Induction Sensitivities in Fresh Hepatocytes from Human Donors, Sprague-Dawley Rats, and Rhesus Monkeys and HepG2 Cells

Silkworth, Jay B.; Koganti, Aruna; Illouz, Kati; Possolo, Antonio; Zhao, Ming; Hamilton, Stephen B.

doi:10.1093/toxsci/kfi261

Cited by 85 publications

(48 citation statements)

References 39 publications

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“…In addition, because the induction of CYP1A1 is minimal in human livers (Xu et al, 2000;Silkworth et al, 2005) and deltamethrin is predominately metabolized by esterases in humans, CYP1A1 metabolism is less interesting for the purposes of this study. Because of the minimal metabolism of both deltamethrin and esfenvalerate by human CYP3A4, kinetic parameters were not determined for this P450.…”

Section: Resultsmentioning

confidence: 99%

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Godin

Crow²,

Scollon³

et al. 2007

Drug Metab Dispos

123

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ABSTRACT:The metabolism of (␣S)-cyano-3-phenoxybenzyl (1R, 3R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (deltamethrin) and (␣S)-cyano-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutyrate (esfenvalerate) by rat and human liver microsomes differs with respect to the biotransformation pathway (oxidation versus hydrolysis) responsible for their clearance. This study aims to further explore the species differences in the metabolism of these chemicals. Using a parent depletion approach, rat and human cytochromes P450 (P450s) were screened for their ability to eliminate deltamethrin or esfenvalerate during in vitro incubations. Rat P450 isoforms CYP1A1, CYP2C6, CYP2C11, and CYP3A2 and human P450 isoforms CYP2C8, CYP2C19, and CYP3A5 were capable of metabolizing either pyrethroid. Human CYP2C9 metabolized esfenvalerate but not deltamethrin. Rat and human P450s that metabolize esfenvalerate and deltamethrin do so with similar kinetics. In addition to the liver, a potential site of metabolic elimination of pyrethroids is the blood via serum carboxylesterase (CE) hydrolysis. The serum of rats, but not humans, contains significant quantities of CE. Deltamethrin and esfenvalerate were metabolized effectively by rat serum and a purified rat serum CE. In contrast, neither pyrethroid was metabolized by human serum or purified human serum esterases (acetylcholinesterase and butyrylcholinesterase). These studies suggest that the difference in rates of oxidative metabolism of pyrethroids by rat and human hepatic microsomes is dependent on the expression levels of individual P450 isoforms rather than their specific activity. Furthermore, these studies show that the metabolic elimination of deltamethrin and esfenvalerate in blood may be important to their disposition in rats but not in humans.

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Section: Resultsmentioning

confidence: 99%

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Godin

Crow²,

Scollon³

et al. 2007

Drug Metab Dispos

123

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“…Previously, Silkworth et al (2005) found that human cells are about 10-1000 times less sensitive to TCDD, PCB-126, and Aroclor 1254 than are rat and monkey cells. Importantly, the newly calculated rat-human interspecies relative potency factors for PCB-126 were more than 100 times lower than the current rodent-derived value (Silkworth et al, 2005).…”

Section: (C) Validation In Experimental Systemsmentioning

confidence: 98%

“…AhR activation by DL-PCBs has been reported in many studies in vitro and in vivo, including comparative toxicogenomic analyses in primary human, monkey, and rodent hepatocytes (Silkworth et al, 2005;Westerink et al 2008). In a comparative in-vitro study in primary cultures of human and rat hepatocytes exposed to TCDD or PCB-126 at various concentrations for 48 hours, dose-responses and relative effective potencies (REP-values) were calculated for induction of CYP1A1 and other AhR-responsive genes (Carlson et al, 2009).…”

Section: (C) Validation In Experimental Systemsmentioning

confidence: 99%

“…In a comparative in-vitro study in primary cultures of human and rat hepatocytes exposed to TCDD or PCB-126 at various concentrations for 48 hours, dose-responses and relative effective potencies (REP-values) were calculated for induction of CYP1A1 and other AhR-responsive genes (Carlson et al, 2009). Previously, Silkworth et al (2005) found that human cells are about 10-1000 times less sensitive to TCDD, PCB-126, and Aroclor 1254 than are rat and monkey cells. Importantly, the newly calculated rat-human interspecies relative potency factors for PCB-126 were more than 100 times lower than the current rodent-derived value (Silkworth et al, 2005).…”

Section: (C) Validation In Experimental Systemsmentioning

confidence: 99%

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Polychlorinated Biphenyls and Polybrominated Biphenyls

Agudo

Aronson²,

Bonefeld-Jörgensen³

et al. 2008

Organic Pollutants

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initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in carcinogenesis and related fields; and to indicate where additional research efforts are needed. The lists of IARC evaluations are regularly updated and are available on the Internet at http:// monographs.iarc.fr/.This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the European Commission Directorate-General for Employment, Social Affairs, and Inclusion, initially by the Unit of Health, Safety and Hygiene at Work, and since 2014 by the European Union Programme for Employment and Social Innovation "EaSI" (2014-2020) The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications -whether for sale or for non-commercial distribution -should be addressed to the IARC Communications Group at: publications@iarc.fr.The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data NOTE TO THE READERThe term 'carcinogenic risk' in the IARC Monographs series is taken to mean that an agent is capable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presence of the word 'risks' in the title.Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that...

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“…Whether the mechanistic relationship of PCBs to tumorigenesis in animals is due solely to aryl hydrocarbon hydroxylase pathways also remains speculative; non -aryl hydrocarbon hydroxylaseinducing congeners can behave as tumor promoters (104). The TEF approach assumes that there is no interspecies difference in toxicity, which is not true (105,106), and some data show that humans are less sensitive than rodents (107). Also, enzymatic induction can vary depending on tissue and dose (108).…”

Section: Toxic Equivalency Factorsmentioning

confidence: 99%

Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls

Shields

2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Decisions about how to improve or protect the public health can be, and sometimes necessarily are, made on imprecise science. The regulation of potential human carcinogens in the environment entails a population-risk assessment process intended to reduce risks to less than one additional cancer in 100,000 or 1,000,000 persons. These risk assessment processes, however, may be miscommunicated or misinterpreted in the context of individual cancer risks by scientists, regulators, the lay media, and the public. This commentary will review methods for establishing a causal relationship between carcinogen exposures and cancer risk. It will use the case of polychlorinated biphenyls (PCB) as an example of how to place scientific data into the context of human exposure and cancer risk. PCBs are widespread environmental contaminants and most people have detectable levels of PCBs in their bodies. The primary source for exposure in the general population is through the diet. PCBs are carcinogens in experimental animal models, but how this information can be extrapolated to human risk remains uncertain. PCB experimental studies provide data that are used to regulate and control human exposure, although the epidemiologic evidence fails to establish PCBs as human carcinogens. Thus, what is used for populationrisk assessment may not be appropriate for individual-risk assessment or concluding that a causal relationship exists between PCB exposure and cancer risk. The hazards from a carcinogen designated by regulatory and review agencies as a ''probable'' human carcinogen is often misunderstood out of context about the magnitude of the risk and in what settings. How scientists communicate their results in scientific articles can strongly influence how others interpret their data. Misunderstandings from both the use of regulatory and review-agency opinions and the conclusions espoused by scientists occur in the media, among private physicians counseling their patients about cancer risk, and in the legal settings where plaintiffs seek compensation for exposure and alleged harm (or future harm). This can lead to false conclusions about what caused a cancer in a specific patient, undue anxiety about future cancer risk, inappropriate cancer screening, and attendant increased morbidity due to increased uses of the medical system and complication rates from medical procedures. The communication of research findings by scientists must be presented with caution, resisting the temptation to extrapolate, inappropriately, research data to the general population. (Cancer Epidemiol Biomarkers Prev 2006;15(5):830 -9)

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Comparison of TCDD and PCB CYP1A Induction Sensitivities in Fresh Hepatocytes from Human Donors, Sprague-Dawley Rats, and Rhesus Monkeys and HepG2 Cells

Cited by 85 publications

References 39 publications

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Polychlorinated Biphenyls and Polybrominated Biphenyls

Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls

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