N＇-nitrosonornicotine　(NNN)　is　one　of　the　tobacco-specific　nitrosamines　(TSNAs)　that　exists　widely　in　smoke　and　smokeless　tobacco　products.　NNN　can　induce　tumors　in　various　laboratory　animal　models　and　has　been　identified　by　International　Agency　for　Research　on　Cancer　(IARC)　as　a　human　carcinogen.　Metabolic　activation　of　NNN　is　primarily　initiated　by　cytochrome　P450　enzymes　(CYP450s)　via　2-hydroxylation　or　5-hydroxylation.　Subsequently,　the　hydroxylating　intermediates　undergo　spontaneous　decomposition　to　generate　diazohydroxides,　which　can　be　further　converted　to　alkyldiazonium　ions,　followed　by　attacking　DNA　to　form　various　DNA　damages,　such　as　pyridyloxobutyl　(POB)-DNA　adducts　and　pyridyl-N-pyrrolidinyl　(py-py)-DNA　adducts.　If　not　repaired　correctly,　these　lesions　would　lead　to　tumor　formation.　In　the　present　study,　we　performed　density　functional　theory　(DFT)　computations　and　molecular　docking　studies　to　understand　the　mechanism　of　metabolic　activation　and　carcinogenesis　of　NNN.　DFT　calculations　were　performed　to　explore　the　2-　or　5-　hydroxylation　reaction　of　(R)-NNN　and　(S)-NNN.　The　results　indicated　that　NNN　catalyzed　by　the　ferric　porphyrin　(Compound　I,　Cpd　I)　at　the　active　center　of　CYP450　included　two　steps,　hydrogen　abstraction　and　rebound　reactions.　The　free　energy　barriers　of　the　2-　and　5-hydroxylation　of　NNN　are　9.82/8.44　kcal/mol　(R/S)　and　7.99/9.19　kcal/mol　(R/S),　respectively,　suggesting　that　the　2-(S)　and　5-(R)　pathways　have　a　slight　advantage.　The　free　energy　barriers　of　the　decomposition　occurred　at　the　2-position　and　5-position　of　NNN　are　18.04/18.02　kcal/mol　(R/S)　and　18.33/19.53　kcal/mol　(R/S),　respectively.　Moreover,　we　calculated　the　alkylation　reactions　occurred　at　ten　DNA　base　sites　induced　by　the　2-hydroxylation　product　of　NNN,　generating　the　free　energy　barriers　ranging　from　0.86　to　4.72　kcal/mol,　which　indicated　that　these　reactions　occurred　easily.　The　docking　study　showed　that　(S)-NNN　had　better　affinity　with　CYP450s　than　that　of　(R)-NNN,　which　was　consistent　with　the　experimental　results.　Overall,　the　combined　results　of　the　DFT　calculations　and　the　docking　obtained　in　this　study　provide　an　insight　into　the　understanding　of　the　carcinogenesis　of　NNN　and　other　TSNAs.