The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism

Metabolism of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-p yridyl)-1-butanone (NNK) in rats was compared to metabolism in primary lung and liver cells. Untreated rats and rats pretreated with phenobarbital, ac etone or phenethyl isothiocyanate (PEITC) were used for all experiments. Al so the influence of [-]-1-methyl-2-[3-pyridyl]-pyrrolidine (nicotine) admin istered concomitantly with NNK, or incubated with isolated cells, upon NNK metabolism was investigated and found to be only marginal upon alpha-hydrox ylation and pyridine N-oxidation in vivo. In hepatocytes nicotine inhibited NNK pyridine N-oxidation, alpha-hydroxylation and glucuronidation of 4-(me thylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), whereas in lung cells the influence of nicotine was not as pronounced. In vivo phenobarbital induced cl-hydroxylation and pyridine N-oxidation. In vitro the effects of the modu lators were most pronounced upon hepatocytes, where phenobarbital greatly i nduced pyridine N-oxidation and PEITC inhibited alpha-hydroxylation. NNAL w as conjugated to its beta-glucuronide in lung cells at four times higher ra tes than in hepatocytes. The ratios of the sum of N-oxides to the sum of al pha-hydroxylation products in vivo were similar to those in lung cells, esp ecially at low NNK concentrations (1 mu M), while in hepatocytes alpha-hydr oxylation was more pronounced. The same correlation of metabolism in isolat ed lung cells with whole rats was observed if oxidative NNAL metabolism was related to oxidative NNK metabolism. Here hepatocytes showed a much higher formation of NNAL oxidation products than either lung cells formed, or rat s excreted in urine. This was true despite a lower rate of metabolism in th e lung than in liver if based on cell number, the rate based on mg protein was four times higher in lung than liver. Only after phenobarbital treatmen t was the contribution of hepatic metabolism to excreted metabolites import ant. In conclusion the lung which is also the target of NNK carcinogenesis, and not the liver, is the organ with the most important contribution to NN K and NNAL metabolism at concentrations relevant to human Exposure. (C) 199 9 Elsevier Science Ireland Ltd. All rights reserved.