TY - JOUR T1 - Comparative Metabolism of the Tobacco-Related Carcinogens Benzo[<em>a</em>]pyrene, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, and<em>N</em>′-Nitrosonornicotine in Human Hepatic Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 154 LP - 162 VL - 25 IS - 2 AU - Marianne E. Staretz AU - Sharon E. Murphy AU - Christopher J. Patten AU - Maria G. Nunes AU - Werner Koehl AU - Shantu Amin AU - Leeann A. Koenig AU - F. Peter Guengerich AU - Stephen S. Hecht Y1 - 1997/02/01 UR - http://dmd.aspetjournals.org/content/25/2/154.abstract N2 - We compared the metabolism in human hepatic microsomes of three tobacco smoke carcinogens believed to be involved in the induction of cancer in humans: benzo[a]pyrene (BaP),4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), andN′-nitrosonornicotine (NNN). The metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, was also investigated. Although the metabolism of some of these compounds by human enzymes or tissue preparations has been previously examined in some studies, they have never been compared in the same human hepatic samples. Moreover, there have been no previous reports of NNAL metabolism by human tissues or enzymes. The tritium-labeled carcinogens (3 μM) were incubated with 10 different human hepatic microsomal preparations and cofactors for 10–20 min, and the products were analyzed by radioflow HPLC. NNN was the best substrate for oxidative metabolism, with the 5′-hydroxylation pathway being the predominant one observed (mean ± SD = 31 ± 17 pmol/min/mg protein). α-Hydroxylation of NNK by the methylene and methyl hydroxylation metabolic activation pathways was the next fastest reaction, with rates of 3.1 ± 1.9 and 3.3 ± 1.1 pmol/min/mg protein, respectively. Metabolism of BaP resulted in the formation of dihydrodiols and phenols;trans-7,8-dihydro-7,8-dihydroxy-BaP, its major proximate carcinogen, was formed at a rate of 1.1 ± 0.61 pmol/min/mg protein. α-Hydroxylation of NNAL proceeded at a rate of 0.53 ± 0.26 pmol/min/mg protein. The results of this study demonstrate that human hepatic microsomes metabolize all of these tobacco carcinogens resulting in a substantial stream of electrophilic intermediates capable of binding to DNA. The relative rates of oxidative metabolism to electrophiles or their precursors were NNN &gt; NNK &gt; BaP &gt; NNAL. Correlation studies indicated involvement of cytochrome P4502A6 in the 5′-hydroxylation of NNN and cytochrome P4503A4 in the α-methylene hydroxylation and pyridine-N-oxidation of NNK and NNAL. The results of this study provide the first data on the comparative metabolism of these important carcinogens in human hepatic microsomes. The American Society for Pharmacology and Experimental Therapeutics ER -