INHIBITION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE MOUSE LUNG TUMORIGENESIS BY ARYLALKYNES, MECHANISM-BASED INACTIVATORS OF CYTOCHROME-P450

Arylalkynes such as 4-phenyl-1-butyne (PBY), 5-phenyl-1-pentyne (PPY) and 2-ethynylnaphthalene (2-EN) are suicide inhibitors of cytochrome P 450 enzymes. Arylalkyl isothiocyanates such as 6-phenylhexyl isothiocy anate (PHITC) are structurally related to arylalkynes and are known to inhibit the cytochrome P450 mediated metabolic activation and tumorig enicity of a tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1 -(3-pyridyl)-1-butanone (NNK). In this study, we compared the ability of PBY, PPY, 2-EN and PHITC to inhibit A/J mouse tung tumorigenesis by NNK. Groups of 20 female mice were gavaged with 5 mumol of arylalkyne or PHITC in corn oil. Two hours tater they were given a single i.p. i njection of 10 mumol NNK. The mice were killed 16 weeks later. PPY and PHITC were both potent inhibitors of tumorigenesis by NNK, reducing l ung tumor multiplicity from 8.35 tumors per mouse to 0.40 and 0.35 res pectively. PBY and 2-EN also significantly inhibited tumor multiplicit y. The results of this study demonstrate that arylalkynes and PHITC ar e potent inhibitors of NNK induced lung tumorigenesis in A/J mice, con sistent with the hypothesis that inhibition of specific cytochrome P45 0 enzymes is involved in inhibition of tumorigenesis.