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The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450
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 substra...
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| Format: | Thesis |
| Language: | English |
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Division of Medical Biochemistry and Structural Biology
2018
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| _version_ | 1867613505202421760 |
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| access_status_str | Open Access |
| author | Van den Honert, Leonard Howard |
| author2 | Ivanetich, Kathryn M |
| author_browse | Ivanetich, Kathryn M Van den Honert, Leonard Howard |
| author_facet | Ivanetich, Kathryn M Van den Honert, Leonard Howard |
| author_sort | Van den Honert, Leonard Howard |
| collection | Thesis |
| description | 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. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/27270 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:37:12.885Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2018 |
| publishDateRange | 2018 |
| publishDateSort | 2018 |
| publisher | Division of Medical Biochemistry and Structural Biology |
| publisherStr | Division of Medical Biochemistry and Structural Biology |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/27270 The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 Van den Honert, Leonard Howard Ivanetich, Kathryn M Cytochrome P-450 Lidocaine Mepivacaine Bupivacaine 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. 2018-02-05T12:42:23Z 2018-02-05T12:42:23Z 1981 Master Thesis Masters MSc (Med) http://hdl.handle.net/11427/27270 eng application/pdf Division of Medical Biochemistry and Structural Biology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Cytochrome P-450 Lidocaine Mepivacaine Bupivacaine Van den Honert, Leonard Howard The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| thesis_degree_str | Master's |
| title | The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| title_full | The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| title_fullStr | The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| title_full_unstemmed | The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| title_short | The interaction of three local anaesthetic agents with hepatic microsomal cytochrome P-450 |
| title_sort | interaction of three local anaesthetic agents with hepatic microsomal cytochrome p 450 |
| topic | Cytochrome P-450 Lidocaine Mepivacaine Bupivacaine |
| url | http://hdl.handle.net/11427/27270 |
| work_keys_str_mv | AT vandenhonertleonardhoward theinteractionofthreelocalanaestheticagentswithhepaticmicrosomalcytochromep450 AT vandenhonertleonardhoward interactionofthreelocalanaestheticagentswithhepaticmicrosomalcytochromep450 |