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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a major metabolite of the tobacco-specific lung carcino- gen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNAL has a chiral center at the 1-position, but little is known about the stereochemical aspects of its metabolic formation from NNK or its further metabolism. We investigated the metabolism of NNK to enantiomers of NNAL in microsomes and cytosol from male F-344 rat liver and lung, female A/J mouse liver and lung, and human liver, as well as in red blood cells from rats, mice and humans. In all systems, (S)-NNAL was the predominant enantiomer formed, ranging from 90 to 98% in the rodent tissues and averaging 64, 90 and >95% in human liver microsomes, liver cytosol and red blood cells, respectively. In rat liver microsomes, (R)- and (S)-NNAL were metabolized at similar rates by alpha-hydroxylation, considered to be the major metabolic activation pathway of NNAL. Pyridine-N-oxidation and adenosine dinucleotide phosphate adduct formation also occurred at similar rates from both enantiomers, while reoxidation to NNK was favored with (S)-NNAL as substrate. In rat lung microsomes, (S)-NNAL was more rapidly metabolized than (R)-NNAL by all oxidative pathways. In human liver microsomes, there were no significant differences in the rates of alpha-hydroxylation, pyridine-N-oxidation and reoxidation to NNK between the two enantiomers. The results of this study demonstrate that (S)-NNAL, the more tumorigenic enantiomer in mice, is preferentially formed from NNK in rodent and human tissues, and is a substrate for oxidative metabolism in rodent and human tissue microsomes.