Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13

Potential for chemoprevention in smokers

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

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Isothiocyanates have been shown to be potent inhibitors of carcinogenesis in animals exposed to a number of chemical carcinogens including the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study the effects of benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), two naturally occuring isothiocyanates, on P450 2A6 and 2A13 were investigated. P450s 2A6 and 2A13 are thought to be the primary human P450 enzymes responsible for the in vivo metabolism of nicotine and NNK, respectively. vitro, BITC and PEITC efficiently inhibited P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. The inhibition of P450 2A6 and 2A13 by BITC was non-competitive with K1's of 4.1 and 1.3 μM, respectively. PEITC was a more potent inhibitor of both enzymes than BITC, with a KI of 0.37 μM for P450 2A6 and 0.03 μM for P450 2A13. P450 2A6-mediated metabolism of nicotine and P450 2A13-mediated α-hydroxylation of NNK were also inhibited significantly by these two isothiocyanates. Both BITC and PEITC were able to inactivate P450 2A6 and 2A13 in an NADPH-dependent manner potentially through the formation of adducts to the apoprotein. The potent inhibition of P450 2A6- and 2A13-mediated metabolisms together with the ability of BITC and PEITC to inactivate the enzymes suggests the possibility that these isothiocyanates could be developed as chemopreventive agents to protect smokers who are unwilling or unable to quit smoking against lung cancer.

Original languageEnglish (US)
Pages (from-to)782-790
Number of pages9
JournalCarcinogenesis
Volume27
Issue number4
DOIs
StatePublished - Apr 1 2006

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Chemoprevention
Isothiocyanates
Hydroxylation
Nicotine
Nitrosamines
Apoproteins
Aptitude
Enzyme Inhibitors
NADP
Carcinogens
Cytochrome P-450 Enzyme System
Tobacco
benzyl isothiocyanate
phenethyl isothiocyanate
Lung Neoplasms
Carcinogenesis
Smoking
Enzymes

Cite this

Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13 : Potential for chemoprevention in smokers. / von Weymarn, Linda B; Chun, Jamie A.; Hollenberg, Paul F.

In: Carcinogenesis, Vol. 27, No. 4, 01.04.2006, p. 782-790.

Research output: Contribution to journalArticle

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