The effect of N'-nitrosoanatabine (NAT) and nicotine on the metabolism of N'-nitrosonornicotine (NNN) and 4-(methyl-nitrosamino)-1-(3- pyridyl)-1-butanone (NNK) by cultured rat oral tissue was investigated. The effect of NNN on NNK metabolism and the effect of NNK on NNN metabolism was also determined. NNK inhibited NNN metabolism more than NNN inhibited NNK metabolism. NAT inhibited the metabolism of NNK but not of NNN. Nicotine, which is present at greater than 500 times the levels of NNN and NNK in smokeless tobacco, inhibited the metabolism of both nitrosamines. Inhibition of 1 microM NNN metabolism was greater than that of 1 microM NNK when the concentration of nicotine was 1, 10 or 100 microM. Nicotine at 100 microM inhibited the formation of all metabolites of NNN by 85-92%. These results suggest that NNN and nicotine may be metabolized by a common enzyme.