Comparison of the Formation of N-Alkylprotoporphyrin IX after Interaction of Porphyrinogenic Xenobiotics with Single cDNA-Expressed Human P450 Enzymes in Microsomes Prepared from Baculovirus-Infected Insect Cells and Human Lymphoblastoid Cell Lines+

Gamble, Jeremy T.; Nakatsu, Kanji; Marks, Gerald S.

doi:10.1124/dmd.31.2.202

Cited by 3 publications

(1 citation statement)

References 11 publications

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“…In their DMD publications, the Marks group used sex differences and selective inducers and inhibitors to identify the specific rat liver P450 sources of N-alkylPP formation from various porphyrinogenic xenobiotics (McNamee and Marks, 1996;Wong et al, 1998;Wong et al, 1999). As well, expressed recombinant human P450s were used to identify the targets for mechanism-based inactivation (McNamee et al, 1997) and the sources of N-alkylPP formation from porphyrinogenic xenobiotics (Lavigne et al, 2002;Gamble et al, 2003). The inhibitory potency of N-methylPP toward human vs. chicken ferrochelatase was also compared (Gamble et al, 2000).…”

Section: University Of Toronto (U Of T)mentioning

confidence: 99%

Canadian Content in the Pages of Drug Metabolism and Disposition: A Comprehensive Historical Analysis

Riddick

2024

Drug Metabolism and Disposition

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Scientists from Canadian institutions have a rich history of making interesting and important contributions to the journal Drug Metabolism and Disposition (DMD) over the past 51 years. A goal of this minireview is to highlight these contributions and pay tribute to many of the scientists at Canadian institutions that have aided in the evolution of the discipline through their DMD publications. We conducted a geographical and research sectoral analysis of the temporal trends of DMD publications originating from Canadian sources. The fraction of total DMD papers of Canadian origin achieved a peak during the 1990s and since that time, this metric has displayed a pronounced and steady decline to the present situation, where the country needs to be concerned about its potentially vulnerable global status within the realm of drug metabolism and disposition science. Stronger and timely investment by Canadian academic institutions in drug metabolism and disposition science may help to restore the nation's research excellence in this discipline and ensure a more robust pipeline of appropriately trained scientists to take on careers in academia, industry, and government. Significance StatementThe substantial contributions made by scientists at Canadian institutions to the journal Drug Metabolism and Disposition (DMD) are highlighted and celebrated in this minireview.Analysis of temporal trends in the fraction of total DMD papers of Canadian origin paints a concerning picture of Canada's current global status in the realm of drug metabolism and disposition science. Further investment in this discipline at Canadian universities may be needed.

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Section: University Of Toronto (U Of T)mentioning

confidence: 99%

Canadian Content in the Pages of Drug Metabolism and Disposition: A Comprehensive Historical Analysis

Riddick

2024

Drug Metabolism and Disposition

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Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes

Zhang

Zheng

et al. 2015

J Biol Inorg Chem

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4-Alkyl-substituted 1,4-dihydropyridines (DHP) exhibit inhibitory activity toward certain cytochrome P450 enzymes (P450) during their biotransformation by these enzymes, which is called mechanism-based inactivation. Though much experimental evidence had proved the essentiality of alkyl radical for P450 inactivation, the underlying mechanism of such radical formation remains elusive. In the present study, density functional calculations were employed to investigate the dealkylation mechanism of 4-alkyl-substituted DHPs mediated by P450. Interestingly, our results indicate that the initial N-H activation proceeds via a proton-coupled electron transfer process, not via the long presumed hydrogen atom transfer mechanism or the stepwise electron transfer/proton transfer one, to form the amino radical and Cpd II complex. Subsequently, homolytic C-C bond cleavage at the 4-position occurs to afford the product complex involving an alkyl radical, an aromatic pyridine derivative. This C-C cleavage step is rate determining for the whole metabolic reaction, with an energy barrier of 7.9/7.9 kcal/mol on the quartet/doublet state, to which aromatization contributes as an essential intrinsic driving force. The 4-substituent groups induce differences in activation energy barriers and in the transition state structures of hydrogen abstraction process. The substrate reactivity correlates well with the stability of the generated alkyl radical as well as the C-C bond dissociation energy. Understanding the metabolic mechanism of DHP analogs is indeed essential for the related design of safer and more efficient drugs. Furthermore, our findings also enrich the mechanistic picture of amine oxidation catalyzed by P450.

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Toxicological Significance of Mechanism-Based Inactivation of Cytochrome P450 Enzymes by Drugs

Masubuchi

Horie

2007

Critical Reviews in Toxicology

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Cytochrome P450 (P450) enzymes oxidize xenobiotics into chemically reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Many clinically important drugs are mechanism-based inactivators that include macrolide antibiotics, calcium channel blockers, and selective serotonin uptake inhibitors, but are not always structurally and pharmacologically related. The inactivation of P450s during drug therapy results in serious drug interactions, since irreversibility of the binding allows enzyme inhibition to be prolonged after elimination of the causal drug. The inhibition of the metabolism of drugs with narrow therapeutic indexes, such as terfenadine and astemizole, leads to toxicities. On the other hand, the fate of P450s after the inactivation and the toxicological consequences remains to be elucidated, while it has been suggested that P450s modified and degraded are involved in some forms of tissue toxicity. Porphyrinogenic drugs, such as griseofulvin, cause mechanism-based heme inactivation, leading to formation of ferrochelatase-inhibitory N-alkylated protoporphyrins and resulting in porphyria. Involvement of P450-derived free heme in halothane-induced hepatotoxicity and catalytic iron in cisplatin-induced nephrotoxicity has also been suggested. Autoantibodies against P450s have been found in hepatitis following administration of tienilic acid and dihydralazine. Tienilic acid is activated by and covalently bound to CYP2C9, and the neoantigens thus formed activate immune systems, resulting in the formation of an autoantibodydirected against CYP2C9, named anti-liver/kidney microsomal autoantibody type 2, whereas the pathological role of the autoantibodies in drug-induced hepatitis remains largely unknown.

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Comparison of the Formation of N-Alkylprotoporphyrin IX after Interaction of Porphyrinogenic Xenobiotics with Single cDNA-Expressed Human P450 Enzymes in Microsomes Prepared from Baculovirus-Infected Insect Cells and Human Lymphoblastoid Cell Lines+

Cited by 3 publications

References 11 publications

Canadian Content in the Pages of Drug Metabolism and Disposition: A Comprehensive Historical Analysis

Canadian Content in the Pages of Drug Metabolism and Disposition: A Comprehensive Historical Analysis

Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes

Toxicological Significance of Mechanism-Based Inactivation of Cytochrome P450 Enzymes by Drugs

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