{"id":{"repo_id":"de-montfort","oai_identifier":"oai:dora.dmu.ac.uk:2086/24656"},"canonical_url":"https://search.dev.ndltd.org/etd/de-montfort/oai:dora.dmu.ac.uk:2086/24656","repository":{"repo_id":"de-montfort","name":"De Montfort University","base_url":"https://dora.dmu.ac.uk/server/oai/request"},"display":{"title":"Studies on pro-oxidant cytochrome P450 enzymes as drug discovery tools and the discovery that they also have a dual function as antioxidants","abstract":"The baker’s yeast Saccharomyces cerevisiae is a unicellular eukaryotic. It has been widely used for heterologous expression of proteins from human cells which are multicellular eukaryotes. Expression of human proteins in yeast has led to (a) production of biopharmaceuticals (b) generation of molecular tools that enable drug discovery involving screening of libraries of small molecular weight chemical compounds (MW < 500 Dalton). Since the intracellular architecture of baker’s yeast cells closely resembles that of human cells, it is considered as a model used for the production of human proteins, identifying and further clarifying complex human biochemical pathways that play vital roles in human cells. In this research, specific cytochrome P450s (CYPs) have been overexpressed in baker’s yeast with the following objectives in mind. (i) CYP1A1, CYP1A2, and CYP1B1 are enzymes highly up-regulated in lung cancers that are caused by inhaling or coming into contact with polyaromatic hydrocarbons (PAHs) which exist in cigarette smoke, in the close proximity to petrochemical industries and in environments which are highly polluted (specifically in mega-cities). There is a need for identifying CYP1A1, CYP1A2, and CYP1B1 inhibitors that would prevent the conversion (mediated by CYPs enzymes) of PAHs to active carcinogens. Hence, these CYPs have been expressed in yeast to devise a cellular system which produces very high levels of CYP activities. This system has been validated using known CYP inhibitors. Hence, it can be used to identify potential inhibitors of CYPs from libraries of chemical compounds. (ii) CYP1A2, CYP2C19, CYP2D6, CYP2C9 and CYP3A4 are major liver enzymes that are widely used to study drug metabolism (i.e. metabolism of medicines). These particular CYPs metabolise medicines into more polar substances through such reactions as hydroxylation etc. Hence, CYPs are thought to function as pro-oxidants, allowing addition of oxygen to unreactive carbon atoms. However, CYPs also act as electron sinks, indicating that it may inherently possess anti-oxidant properties. This has never been investigated before. This was probed using ethanol-treated yeast cells which are blocked in cell growth. In both yeast and human cells, ethanol is known to induce apoptosis which is generally triggered by reactive oxygen species (pro-oxidants) stemming from reactions between free electrons within cells and molecular oxygen, O2. Observations indicated that these CYPs do restore yeast cell growth that has been blocked by 5 % ethanol. (iii) Human Bax protein is probably the most dominant pro-apoptotic protein (inducer of apoptosis) existing within human cells. It has been widely used to understand the human features of apoptosis in yeast. Observations indicated that CYPs rescue the block of cell growth induced by Bax in yeast, again indicating that a CYP has the potential to act as an anti-oxidant too.","abstract_html":"The baker’s yeast Saccharomyces cerevisiae is a unicellular eukaryotic. It has been widely used for heterologous expression of proteins from human cells which are multicellular eukaryotes. Expression of human proteins in yeast has led to (a) production of biopharmaceuticals (b) generation of molecular tools that enable drug discovery involving screening of libraries of small molecular weight chemical compounds (MW &lt; 500 Dalton). Since the intracellular architecture of baker’s yeast cells closely resembles that of human cells, it is considered as a model used for the production of human proteins, identifying and further clarifying complex human biochemical pathways that play vital roles in human cells. In this research, specific cytochrome P450s (CYPs) have been overexpressed in baker’s yeast with the following objectives in mind. (i) CYP1A1, CYP1A2, and CYP1B1 are enzymes highly up-regulated in lung cancers that are caused by inhaling or coming into contact with polyaromatic hydrocarbons (PAHs) which exist in cigarette smoke, in the close proximity to petrochemical industries and in environments which are highly polluted (specifically in mega-cities). There is a need for identifying CYP1A1, CYP1A2, and CYP1B1 inhibitors that would prevent the conversion (mediated by CYPs enzymes) of PAHs to active carcinogens. Hence, these CYPs have been expressed in yeast to devise a cellular system which produces very high levels of CYP activities. This system has been validated using known CYP inhibitors. Hence, it can be used to identify potential inhibitors of CYPs from libraries of chemical compounds. (ii) CYP1A2, CYP2C19, CYP2D6, CYP2C9 and CYP3A4 are major liver enzymes that are widely used to study drug metabolism (i.e. metabolism of medicines). These particular CYPs metabolise medicines into more polar substances through such reactions as hydroxylation etc. Hence, CYPs are thought to function as pro-oxidants, allowing addition of oxygen to unreactive carbon atoms. However, CYPs also act as electron sinks, indicating that it may inherently possess anti-oxidant properties. This has never been investigated before. This was probed using ethanol-treated yeast cells which are blocked in cell growth. In both yeast and human cells, ethanol is known to induce apoptosis which is generally triggered by reactive oxygen species (pro-oxidants) stemming from reactions between free electrons within cells and molecular oxygen, O2. Observations indicated that these CYPs do restore yeast cell growth that has been blocked by 5 % ethanol. (iii) Human Bax protein is probably the most dominant pro-apoptotic protein (inducer of apoptosis) existing within human cells. It has been widely used to understand the human features of apoptosis in yeast. Observations indicated that CYPs rescue the block of cell growth induced by Bax in yeast, again indicating that a CYP has the potential to act as an anti-oxidant too.","abstract_has_math":false,"creators":["Alqahtani, Ali"],"institution":"De Montfort University","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-09","date_published":"2018-09","updated_at":"2026-07-24T06:18:54Z","subjects":[],"languages":[],"rights":[],"rights_urls":["https://dora.dmu.ac.uk/bitstreams/e4ae4a87-3812-4b7f-b7c3-6182e44837ec/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Saudi Arabian Cultural Bureau and King Khaled University"]},{"key":"dc:creator","label":"Author","values":["Alqahtani, Ali"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2018-09"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Faculty of Health and Life Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["De Montfort University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://hdl.handle.net/2086/24656"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://dora.dmu.ac.uk/bitstreams/e4ae4a87-3812-4b7f-b7c3-6182e44837ec/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://dora.dmu.ac.uk/bitstreams/6fee5623-9dde-42bd-859a-99c1c0809a72/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The baker’s yeast Saccharomyces cerevisiae is a unicellular eukaryotic. 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(i) CYP1A1, CYP1A2, and CYP1B1 are enzymes highly up-regulated in lung cancers that are caused by inhaling or coming into contact with polyaromatic hydrocarbons (PAHs) which exist in cigarette smoke, in the close proximity to petrochemical industries and in environments which are highly polluted (specifically in mega-cities). There is a need for identifying CYP1A1, CYP1A2, and CYP1B1 inhibitors that would prevent the conversion (mediated by CYPs enzymes) of PAHs to active carcinogens. Hence, these CYPs have been expressed in yeast to devise a cellular system which produces very high levels of CYP activities. This system has been validated using known CYP inhibitors. Hence, it can be used to identify potential inhibitors of CYPs from libraries of chemical compounds. (ii) CYP1A2, CYP2C19, CYP2D6, CYP2C9 and CYP3A4 are major liver enzymes that are widely used to study drug metabolism (i.e. metabolism of medicines). 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