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Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol - PubMed

  • ️Sun Jan 01 2012

Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, β-nicotyrine and menthol

Valerie M Kramlinger et al. Chem Biol Interact. 2012.

Abstract

Nicotine is the primary addictive agent in tobacco products and is metabolized in humans by CYP2A6. Decreased CYP2A6 activity has been associated with decreased smoking. The extrahepatic enzyme, CYP2A13 (94% identical to CYP2A6) also catalyzes the metabolism of nicotine, but is most noted for its role in the metabolic activation of the tobacco specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, the inhibition and potential inactivation of CYP2A6 and CYP2A13 by two tobacco constituents, 1-methyl-4-(3-pyridinyl) pyrrole (β-nicotyrine) and (-)-menthol were characterized and compared to the potent mechanism based inactivator of CYP2A6, menthofuran. The effect of these compounds on CYP2A6 and CYP2A13 activity was significantly different. (-)-Menthol was a more efficient inhibitor of CYP2A13 than of CYP2A6 (KI, 8.2 μM and 110 μM, respectively). β-Nicotyrine was a potent inhibitor of CYP2A13 (KI, 0.17 μM). Neither menthol nor β-nicotyrine was an inactivator of CYP2A13. Whereas, β-nicotyrine was a mechanism based inactivator of CYP2A6 (KI(inact), 106 μM, kinact was 0.61 min(-1)). Similarly, menthofuran, a potent mechanism based inactivator of CYP2A6 did not inactivate CYP2A13. Menthofuran was an inhibitor of CYPA13 (KI, 1.24 μM). The inactivation of CYP2A6 by either β-nicotyrine or menthofuran was not due to modification of the heme and was likely due to modification of the apo-protein. These studies suggest that β-nicotyrine, but not menthol may influence nicotine and NNK metabolism in smokers.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Conflict of interest statement

Conflict of Interest

The authors declare no financial or commercial conflict of interest.

Figures

Figure 1
Figure 1

Structures of nicotine, β-nicotyrine, (−)- menthol, and menthofuran.

Figure 2
Figure 2. Time and concentration-dependent inactivation of CYP2A6 by menthofuran (A) and β-nicotyrine (B)

Activity remaining refers to coumarin 7-hydroxylation activity determined in a secondary reaction. Details of the experiments are as described in Materials and Methods. The menthofuran concentrations used were 0(●), 1(○), 2.5(▼), 5(▽) and 10(■) μM and the β-nicotyrine concentrations used were 0(●), 5(○), 10(▼), 40(▽) and 80(■) μM. Values are the mean ± S.D. from three independent experiments. The insets represent the double-reciprocal plot generated from the slopes of the lines at the various concentrations.

Figure 3
Figure 3. Partition ratio determination for CYP2A6 with β-nicotyrine (A) and menthofuran (B)

The inactivation was allowed to go to completion, and then coumarin 7-hydroxylation activity was determined in a secondary reaction as described under Materials and Methods. Values are the mean ± S.D. of three independent experiments performed in duplicate. The arrow indicates the intercept used to determine the partition ratio.

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