The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450

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dc.contributor.advisorIvanetich, Kathryn Men_ZA
dc.contributor.authorVan den Honert, Leonard Howarden_ZA
dc.date.accessioned2018-02-05T12:42:23Z
dc.date.available2018-02-05T12:42:23Z
dc.date.issued1981en_ZA
dc.description.abstractThe effect of inducing agents of cytochrome P-450 on the binding and metabolism of three local anaesthetic agents: lidocaine, mepivacaine and bupivacaine has been investigated. All three local anaesthetic agents bound to the type I binding site of cytochrome P-450, which is characteristic of substrate binding to cytochrome P-450, and stimulated the CO-inhibitable oxidation of NADPH. Lidocaine is shown to be metabolized by cytochrome P-450 to the products MEGX and acetaldehyde. The forms of cytochrome P-450 elevated with phenobarbital and/or pregnenolone-16α-carbonitrile were shown to play an important role in the binding of lidocaine to cytochrome P-450. Cytochrome P-448 did not appear to be involved in the binding of lidocaine to cytochrome P-450. These findings are supported by the ability of the inhibitors of cytochrome P-450 viz. metyrapone, SKF 525-A and CO:O₂ to inhibit binding of lidocaine to cytochrome P-450. No single form of cytochrome P-450 appears to preferentially metabolize lidocaine, but rather multiple forms of the enzyme appear to be involved in the metabolism of lidocaine. The phenobarbital inducible form of cytochrome P-450 appears to play a major role in the binding of mepivacaine to cytochrome P-450. Cytochrome P-450 in microsomes from rats pretreated with β-naphthoflavone and pregnenolone-16α-carbonitrile does not appear to have a significant role in the binding of mepivacaine to cytochrome P-450. All forms of cytochrome P-450 are involved in the metabolism of mepivacaine· to metabolic products as assessed by the oxidation of NADPH. However, the form of cytochrome P-450 induced by pretreatment of rats with phenobarbital may play a predominant role in the total metabolism of mepivacaine. Multiple forms of cytochrome P-450 appear to be involved in the binding and total metabolism of bupivacaine. As in the case of mepivacaine, the total metabolism of bupivacaine, as assessed by the oxidation of NADPH, may be predominantly catalyzed by the form of cytochrome P-450 found in microsomes from rats pretreated with phenobarbital. Partially purified cytochrome P-450 was found to bind lidocaine in a type I manner and, in the presence of the artificial electron donor H₂O₂, produce MEGX. This further supports the role of cytochrome P-450 in the in vitro metabolism of lidocaine. Hepatocytes were found to metabolize lidocaine to MEGX, indicating that lidocaine metabolism in vivo might well be mediated by cytochrome P-450.en_ZA
dc.identifier.apacitationVan den Honert, L. H. (1981). <i>The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry & Structural Biology. Retrieved from http://hdl.handle.net/11427/27270en_ZA
dc.identifier.chicagocitationVan den Honert, Leonard Howard. <i>"The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry & Structural Biology, 1981. http://hdl.handle.net/11427/27270en_ZA
dc.identifier.citationVan den Honert, L. 1981. The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Van den Honert, Leonard Howard AB - The effect of inducing agents of cytochrome P-450 on the binding and metabolism of three local anaesthetic agents: lidocaine, mepivacaine and bupivacaine has been investigated. All three local anaesthetic agents bound to the type I binding site of cytochrome P-450, which is characteristic of substrate binding to cytochrome P-450, and stimulated the CO-inhibitable oxidation of NADPH. Lidocaine is shown to be metabolized by cytochrome P-450 to the products MEGX and acetaldehyde. The forms of cytochrome P-450 elevated with phenobarbital and/or pregnenolone-16α-carbonitrile were shown to play an important role in the binding of lidocaine to cytochrome P-450. Cytochrome P-448 did not appear to be involved in the binding of lidocaine to cytochrome P-450. These findings are supported by the ability of the inhibitors of cytochrome P-450 viz. metyrapone, SKF 525-A and CO:O₂ to inhibit binding of lidocaine to cytochrome P-450. No single form of cytochrome P-450 appears to preferentially metabolize lidocaine, but rather multiple forms of the enzyme appear to be involved in the metabolism of lidocaine. The phenobarbital inducible form of cytochrome P-450 appears to play a major role in the binding of mepivacaine to cytochrome P-450. Cytochrome P-450 in microsomes from rats pretreated with β-naphthoflavone and pregnenolone-16α-carbonitrile does not appear to have a significant role in the binding of mepivacaine to cytochrome P-450. All forms of cytochrome P-450 are involved in the metabolism of mepivacaine· to metabolic products as assessed by the oxidation of NADPH. However, the form of cytochrome P-450 induced by pretreatment of rats with phenobarbital may play a predominant role in the total metabolism of mepivacaine. Multiple forms of cytochrome P-450 appear to be involved in the binding and total metabolism of bupivacaine. As in the case of mepivacaine, the total metabolism of bupivacaine, as assessed by the oxidation of NADPH, may be predominantly catalyzed by the form of cytochrome P-450 found in microsomes from rats pretreated with phenobarbital. Partially purified cytochrome P-450 was found to bind lidocaine in a type I manner and, in the presence of the artificial electron donor H₂O₂, produce MEGX. This further supports the role of cytochrome P-450 in the in vitro metabolism of lidocaine. Hepatocytes were found to metabolize lidocaine to MEGX, indicating that lidocaine metabolism in vivo might well be mediated by cytochrome P-450. DA - 1981 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1981 T1 - The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 TI - The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 UR - http://hdl.handle.net/11427/27270 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/27270
dc.identifier.vancouvercitationVan den Honert LH. The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry & Structural Biology, 1981 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/27270en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Medical Biochemistry and Structural Biology
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherCytochrome P-450en_ZA
dc.subject.otherLidocaineen_ZA
dc.subject.otherMepivacaineen_ZA
dc.subject.otherBupivacaineen_ZA
dc.titleThe interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450en_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMSc (Med)en_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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