Induction of cytochromes P450 2B and 2E1 in rat liver by isomeric picoline N-oxides

Murray, Michael T.; Sefton, Rachel M; Martini, Robert; Butler, Alison

doi:10.1016/s0378-4274(97)00092-1

Cited by 9 publications

(6 citation statements)

References 27 publications

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“…These results suggest that N-methylpyridinium ions, and presumably other alkylpyridinium ion as well, enhance the expression and activity of chemopreventive phase I/II enzymes. This hypothesis is also supported by data obtained with other structurally related pyridine derivatives, such as picolines, which are also present in coffee beverages and are known to induce cytochrome P450 (40) and GST (41) isoenzymes.…”

Section: Resultssupporting

confidence: 68%

Activity-Guided Identification of a Chemopreventive Compound in Coffee Beverage Using in Vitro and in Vivo Techniques

Somoza

Lindenmeier²,

Wenzel³

et al. 2003

J. Agric. Food Chem.

124

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The aim of the present study was to apply an activity-guided screening procedure to coffee brew to identify a key chemopreventive compound by means of in vitro antioxidant tests as well as cell culture experiments and to prove the in vivo activity of that compound by an animal feeding experiment. Solvent fractionation, followed by multiple-step ultrafiltration, revealed that the polar coffee compounds with molecular weights below 1 kDa show the major inhibitory effect on the in vitro peroxidation of linoleic acid as well as the predominant chemopreventive enzyme modulating activity on the NADPH-cytochrome c reductase (CCR) and glutathione S-transferase (GST) in human intestinal Caco-2 cells. To identify the chemical structure of the most active antioxidants and chemopreventive compounds, the polar compounds were further separated by HPLC techniques, followed by the activity-guided screening of the individual HPLC fraction. These experiments demonstrated 5-chlorogenic acid to be the most powerful antioxidant in vitro, whereas, in contrast, chemopreventive effects on the GST activity were found for the N-methylpyridinium ion, the structure of which was elucidated by LC-MS and NMR experiments and confirmed by synthesis. The in vivo activities of coffee beverage and N-methylpyridinium ions were tested in a 15-day feeding experiment on rats. In the liver, feeding of 4.5% coffee beverage resulted in increases of GST and UDP-GT activities by 24 and 40% compared to animals fed the control diet (p > 0.05), respectively. Plasma total antioxidant capacity and plasma tocopherol were elevated in animals fed the coffee beverage and the N-methylpyridinium-containing diet. In summary, the results demonstrating a strong in vitro antioxidant activity for coffee were confirmed by the feeding study. Surprisingly, feeding of N-methylpyridinium also resulted in an increased total antioxidant capacity in the plasma. The data indicate that the mode of action demonstrated for N-methylpyridinium in biological systems is different from that in foods.

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Section: Resultssupporting

confidence: 68%

Activity-Guided Identification of a Chemopreventive Compound in Coffee Beverage Using in Vitro and in Vivo Techniques

Somoza

Lindenmeier²,

Wenzel³

et al. 2003

J. Agric. Food Chem.

124

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“…[10] This difference can significantly change the heat effect of the coordination process due to interactions of π-π-type. In accordance with the work of the authors, [9] the stability constants from the NMR data for the reaction:…”

Section: Introductionmentioning

confidence: 78%

“…[9] Therefore, identification of the basic laws that determine the stability of the complexes of metalloporphyrins with heterocyclic N-oxides, it is certainly an actual task. The stability of molecular complexes are traditionally determined by the spectrophotometric method and the calorimetric titration.…”

Section: Introductionmentioning

confidence: 99%

Determination of Stability of Molecular Complexes of Zinc(II) meso-Tetraphenylporphyrin with Heterocyclic N-Oxide and Pyridine by Different Methods

Gubarev¹,

Lebedevа²,

Голубев³

et al. 2013

MHC

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“…Eliza, VIC, Australia). Cytochrome c reductase activity was measured spectrophotometrically using methods described previously (Murray et al, 1997).…”

Section: Methodsmentioning

confidence: 99%

Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis

Zhang

Ramzan²,

Murray³

2007

J Pharmacol Exp Ther

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Hepatic lipid infiltration (steatosis) is a complication of the metabolic syndrome and can progress to nonalcoholic steatohepatitis and severe liver injury. Microsomal cytochrome P450 (P450) drug oxidases are down-regulated in experimental steatosis. In this study we evaluated the separate and combined effects of lipid accumulation and P450 down-regulation on the microsomal oxidation of the antipsychotic agent clozapine (CLZ), the use of which is associated with an increased incidence of the metabolic syndrome. Several important drug oxidizing P450s were down-regulated, and the formation of Ndesmethyl-CLZ (norCLZ) and CLZ N-oxide was decreased in microsomal fractions from orotic acid-induced early steatotic rat liver. Inclusion of lipids extracted from steatotic, but not control, liver decreased the free concentration of CLZ in microsomes and suppressed norCLZ formation; CLZ N-oxidation was unchanged. Triglycerides increased in steatotic liver to 15-fold of control, whereas increases in the monounsaturated oleic acid to 10-fold of control and total polyunsaturated and saturated fatty acids to 4-and 5-fold of control also occurred. Addition of triglycerides containing esterified -6 and -3 fatty acids inhibited the microsomal formation of norCLZ but not that of CLZ N-oxide; triglycerides esterified with unsaturated and monounsaturated fatty acids were inactive. Thus, drug oxidation may be suppressed in steatosis by P450 down-regulation and the accumulation of polyunsaturated fatty esters. In contrast, the activity of the flavin-containing monooxygenase that mediates CLZ N-oxidation was unimpaired. Lipid deposition in livers of patients with the metabolic syndrome may necessitate dosage adjustments for toxic drugs, including CLZ.

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Induction of cytochromes P450 2B and 2E1 in rat liver by isomeric picoline N-oxides

Cited by 9 publications

References 27 publications

Activity-Guided Identification of a Chemopreventive Compound in Coffee Beverage Using in Vitro and in Vivo Techniques

Activity-Guided Identification of a Chemopreventive Compound in Coffee Beverage Using in Vitro and in Vivo Techniques

Determination of Stability of Molecular Complexes of Zinc(II) meso-Tetraphenylporphyrin with Heterocyclic N-Oxide and Pyridine by Different Methods

Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis

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