Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation

Linda B von Weymarn, Jamie A. Chun, Gabriel A. Knudsen, Paul F. Hollenberg

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16 Citations (Scopus)

Abstract

Many isothiocyanates (ITCs), both naturally occurring and synthetic, are potent and selective inhibitors of carcinogenesis in animal models and are now viewed as a class of promising chemopreventive agents. We have investigated the ability of 11 ITCs to inhibit and/or inactivate P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. Two of these 11 ITCs, phenylpropyl isothiocyanate (PPITC) and phenylhexyl isothiocyanate (PHITC), were potent inhibitors of P450 2A13. The KI values for the inhibition of P450 2A13-mediated coumarin 7-hydroxylation by PPITC and PHITC were approximately 0.14 and 1.1 μM, respectively. P450 2A6 was also inhibited by these two ITCs; however, the K I values indicated they were approximately 10-20-fold less potent for P450 2A6 than for P450 2A13. Most of the ITCs tested, including PPITC and PHITC, showed some degree of inactivation of both P450s; however, only one compound, tert-butyl isothiocyanate (tBITC), showed significant inactivation of P450 2A13 at a concentration of 10 μM. None of the ITCs caused significant inactivation of P450 2A6 at this concentration. tBITC inactivated P450 2A13 with an apparent KI of 4.3 μM and a kinact of 0.94 min -1. Inactivation of P450 2A6 by tBITC was observed only at high concentrations and long incubation times. The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies.

Original languageEnglish (US)
Pages (from-to)1252-1259
Number of pages8
JournalChemical Research in Toxicology
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2007

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Isothiocyanates
Hydroxylation
coumarin 7
isothiocyanic acid
Carcinogenesis
Animals
Animal Models

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Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation. / von Weymarn, Linda B; Chun, Jamie A.; Knudsen, Gabriel A.; Hollenberg, Paul F.

In: Chemical Research in Toxicology, Vol. 20, No. 9, 01.09.2007, p. 1252-1259.

Research output: Contribution to journalArticle

von Weymarn, Linda B ; Chun, Jamie A. ; Knudsen, Gabriel A. ; Hollenberg, Paul F. / Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation. In: Chemical Research in Toxicology. 2007 ; Vol. 20, No. 9. pp. 1252-1259.
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abstract = "Many isothiocyanates (ITCs), both naturally occurring and synthetic, are potent and selective inhibitors of carcinogenesis in animal models and are now viewed as a class of promising chemopreventive agents. We have investigated the ability of 11 ITCs to inhibit and/or inactivate P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. Two of these 11 ITCs, phenylpropyl isothiocyanate (PPITC) and phenylhexyl isothiocyanate (PHITC), were potent inhibitors of P450 2A13. The KI values for the inhibition of P450 2A13-mediated coumarin 7-hydroxylation by PPITC and PHITC were approximately 0.14 and 1.1 μM, respectively. P450 2A6 was also inhibited by these two ITCs; however, the K I values indicated they were approximately 10-20-fold less potent for P450 2A6 than for P450 2A13. Most of the ITCs tested, including PPITC and PHITC, showed some degree of inactivation of both P450s; however, only one compound, tert-butyl isothiocyanate (tBITC), showed significant inactivation of P450 2A13 at a concentration of 10 μM. None of the ITCs caused significant inactivation of P450 2A6 at this concentration. tBITC inactivated P450 2A13 with an apparent KI of 4.3 μM and a kinact of 0.94 min -1. Inactivation of P450 2A6 by tBITC was observed only at high concentrations and long incubation times. The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies.",
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AU - Hollenberg, Paul F.

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N2 - Many isothiocyanates (ITCs), both naturally occurring and synthetic, are potent and selective inhibitors of carcinogenesis in animal models and are now viewed as a class of promising chemopreventive agents. We have investigated the ability of 11 ITCs to inhibit and/or inactivate P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. Two of these 11 ITCs, phenylpropyl isothiocyanate (PPITC) and phenylhexyl isothiocyanate (PHITC), were potent inhibitors of P450 2A13. The KI values for the inhibition of P450 2A13-mediated coumarin 7-hydroxylation by PPITC and PHITC were approximately 0.14 and 1.1 μM, respectively. P450 2A6 was also inhibited by these two ITCs; however, the K I values indicated they were approximately 10-20-fold less potent for P450 2A6 than for P450 2A13. Most of the ITCs tested, including PPITC and PHITC, showed some degree of inactivation of both P450s; however, only one compound, tert-butyl isothiocyanate (tBITC), showed significant inactivation of P450 2A13 at a concentration of 10 μM. None of the ITCs caused significant inactivation of P450 2A6 at this concentration. tBITC inactivated P450 2A13 with an apparent KI of 4.3 μM and a kinact of 0.94 min -1. Inactivation of P450 2A6 by tBITC was observed only at high concentrations and long incubation times. The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies.

AB - Many isothiocyanates (ITCs), both naturally occurring and synthetic, are potent and selective inhibitors of carcinogenesis in animal models and are now viewed as a class of promising chemopreventive agents. We have investigated the ability of 11 ITCs to inhibit and/or inactivate P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. Two of these 11 ITCs, phenylpropyl isothiocyanate (PPITC) and phenylhexyl isothiocyanate (PHITC), were potent inhibitors of P450 2A13. The KI values for the inhibition of P450 2A13-mediated coumarin 7-hydroxylation by PPITC and PHITC were approximately 0.14 and 1.1 μM, respectively. P450 2A6 was also inhibited by these two ITCs; however, the K I values indicated they were approximately 10-20-fold less potent for P450 2A6 than for P450 2A13. Most of the ITCs tested, including PPITC and PHITC, showed some degree of inactivation of both P450s; however, only one compound, tert-butyl isothiocyanate (tBITC), showed significant inactivation of P450 2A13 at a concentration of 10 μM. None of the ITCs caused significant inactivation of P450 2A6 at this concentration. tBITC inactivated P450 2A13 with an apparent KI of 4.3 μM and a kinact of 0.94 min -1. Inactivation of P450 2A6 by tBITC was observed only at high concentrations and long incubation times. The observed differences in inhibition and/or inactivation of P450 2A6 and 2A13 by a few of the isothiocyanates suggest that these compounds may be useful for structure-function studies.

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