{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/78529"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/78529","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Comparing the in vitro human hepatic metabolism of α-cypermethrin (αCM) and λ-cyhalothrin (λ-CH), and the impact of co-exposure to an organophosphate pesticide on biotransformation","abstract":"M.S.","abstract_html":"M.S.","abstract_has_math":false,"creators":["Abdallah, Rula; 0000-0003-3204-6188"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Olson, James","Pharmacology and Toxicology"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-10-26T02:54:54Z","date_published":"2018-10-26T02:54:54Z","updated_at":"2026-07-27T19:05:12Z","subjects":["toxicology"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/78529","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Olson, James","Pharmacology and Toxicology"]},{"key":"dc:creator","label":"Author","values":["Abdallah, Rula; 0000-0003-3204-6188"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-10-26T02:54:54Z","2018","2018-07-27 16:46:26"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["toxicology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/78529"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["M.S.","Pyrethroids (PYRs), including lambda-cyhalothrin (λCH) and alpha-cypermethrin (αCM), are insecticides used in both agricultural and residential settings in the United States and other parts of the world. PYR usage has increased during the past decade with the decline of organophosphate (OP) pesticide usage. Although, OPs, such as chlorpyrifos, are still commonly used throughout the world, they are often applied with type II pyrethroid to increase the effectiveness of insect control. Type II pyrethroid such as λCH and αCM are neurotoxic, acting by prolonging the open time of voltage-gated sodium channels. While little data are available on the human metabolism of λCH and αCM, rodent studies suggest that PYRs are metabolized by cytochrome P-450 (CYP) and carboxylesterase (CE) enzymes, resulting in the formation of inactive metabolites that serve as biomarkers of exposure. The aims of this thesis were to address this data gap by comparing the metabolism of αCM and λ-CH by human liver microsomes and the impact of co-exposure to an OP pesticide on pyrethroid biotransformation. Pooled human liver microsomes were used to assess kinetic parameters (Km and Vmax) for λCH and αCM metabolism, through the formation of non-specific metabolites, 3-phenoxybenzyl alcohol (3PB Alcohol), 3-phenoxybenzoic acid (3-PBA), and the specific metabolites, cis-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA) from αCM and lambda cyhalothric acid (LC acid) from λCH. The formation of 3PB alcohol, 3-PBA and LC acid from λCH had Vmax values of 523, 218, and 923 pmol/min/mg protein, and Km values of 54, 16, and 35 μM, respectively. Similarly, the formation of 3PB alcohol, 3-PBA and cis DCCA from αCM had Vmax values of 700, 333, and 1377 pmol/min/mg protein, and Km values of 35, 17, and 23 respectively. Incubation in the absence of NADPH resulted in a marked reduction in the formation of only 3-PBA and 3-PB alcohol, suggesting that their formation was CYP mediated, while supporting the role of carboxylesterase in mediating the formation of cis-DCCA and lambda cyhalothric acid. Iso-OMPA, a potent esterase inhibitor, was used to assess the impact of carboxylesterase inhibition on the biotransformation reactions. High concentration of iso- OMPA (500 µM) resulted in a reduction in the formation of all metabolites of λCH and αCM, suggesting that carboxylesterase catalyzes the initial step in the biotransformation of λCH and αCM. To assess the impact of co-exposure of αCM and λCH with an OP pesticide, incubations were conducted with chlorpyrifos-Oxon (CPF-O), the active metabolite of chlorpyrifos, which is a potent esterase inhibitor. CPF-O at 100 and 200 nM produced a concentration dependent inhibition in the formation of all metabolites of αCM and λCH. This indicates that combined exposures to PYR and OP insecticides results in a reduced rate of αCM and λCH biotransformation, which can result in slower in vivo clearance and increased toxic potency of the PYR pesticides. These metabolites were also detected in urine samples of Egyptian adolescent agriculture workers that applied λCH and αCM to the cotton fields, thus serving as biomarkers of pesticide exposure. Together, in vivo exposure and in vitro metabolism data can be used in risk assessment for occupational and residential exposures and to assist efforts to assess risk and reduce exposures."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Comparing the in vitro human hepatic metabolism of α-cypermethrin (αCM) and λ-cyhalothrin (λ-CH), and the impact of co-exposure to an organophosphate pesticide on biotransformation"]}]}],"canonical_facts":{"dc:contributor":["Olson, James","Pharmacology and Toxicology"],"dc:creator":["Abdallah, Rula; 0000-0003-3204-6188"],"dc:date":["2018-10-26T02:54:54Z","2018","2018-07-27 16:46:26"],"dc:description":["M.S.","Pyrethroids (PYRs), including lambda-cyhalothrin (λCH) and alpha-cypermethrin (αCM), are insecticides used in both agricultural and residential settings in the United States and other parts of the world. PYR usage has increased during the past decade with the decline of organophosphate (OP) pesticide usage. Although, OPs, such as chlorpyrifos, are still commonly used throughout the world, they are often applied with type II pyrethroid to increase the effectiveness of insect control. Type II pyrethroid such as λCH and αCM are neurotoxic, acting by prolonging the open time of voltage-gated sodium channels. While little data are available on the human metabolism of λCH and αCM, rodent studies suggest that PYRs are metabolized by cytochrome P-450 (CYP) and carboxylesterase (CE) enzymes, resulting in the formation of inactive metabolites that serve as biomarkers of exposure. The aims of this thesis were to address this data gap by comparing the metabolism of αCM and λ-CH by human liver microsomes and the impact of co-exposure to an OP pesticide on pyrethroid biotransformation. Pooled human liver microsomes were used to assess kinetic parameters (Km and Vmax) for λCH and αCM metabolism, through the formation of non-specific metabolites, 3-phenoxybenzyl alcohol (3PB Alcohol), 3-phenoxybenzoic acid (3-PBA), and the specific metabolites, cis-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA) from αCM and lambda cyhalothric acid (LC acid) from λCH. The formation of 3PB alcohol, 3-PBA and LC acid from λCH had Vmax values of 523, 218, and 923 pmol/min/mg protein, and Km values of 54, 16, and 35 μM, respectively. Similarly, the formation of 3PB alcohol, 3-PBA and cis DCCA from αCM had Vmax values of 700, 333, and 1377 pmol/min/mg protein, and Km values of 35, 17, and 23 respectively. Incubation in the absence of NADPH resulted in a marked reduction in the formation of only 3-PBA and 3-PB alcohol, suggesting that their formation was CYP mediated, while supporting the role of carboxylesterase in mediating the formation of cis-DCCA and lambda cyhalothric acid. Iso-OMPA, a potent esterase inhibitor, was used to assess the impact of carboxylesterase inhibition on the biotransformation reactions. High concentration of iso- OMPA (500 µM) resulted in a reduction in the formation of all metabolites of λCH and αCM, suggesting that carboxylesterase catalyzes the initial step in the biotransformation of λCH and αCM. To assess the impact of co-exposure of αCM and λCH with an OP pesticide, incubations were conducted with chlorpyrifos-Oxon (CPF-O), the active metabolite of chlorpyrifos, which is a potent esterase inhibitor. CPF-O at 100 and 200 nM produced a concentration dependent inhibition in the formation of all metabolites of αCM and λCH. This indicates that combined exposures to PYR and OP insecticides results in a reduced rate of αCM and λCH biotransformation, which can result in slower in vivo clearance and increased toxic potency of the PYR pesticides. These metabolites were also detected in urine samples of Egyptian adolescent agriculture workers that applied λCH and αCM to the cotton fields, thus serving as biomarkers of pesticide exposure. Together, in vivo exposure and in vitro metabolism data can be used in risk assessment for occupational and residential exposures and to assist efforts to assess risk and reduce exposures."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/78529"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["toxicology"],"dc:title":["Comparing the in vitro human hepatic metabolism of α-cypermethrin (αCM) and λ-cyhalothrin (λ-CH), and the impact of co-exposure to an organophosphate pesticide on biotransformation"],"dc:type":["Text","Thesis"]},"updated_at":"2026-07-27T19:05:12Z"}