TY - JOUR
T1 - Human cytochrome P450 2S1
T2 - Lack of activity in the metabolic activation of several cigarette smoke carcinogens and in the metabolism of nicotine
AU - Wang, Shou Lin
AU - He, Xiao Yang
AU - Hong, Jun Yan
PY - 2005/3
Y1 - 2005/3
N2 - Cytochrome P450 (P450) enzymes play a critical role in the metabolic activation of a wide variety of environmental carcinogens. Recently, a novel human P450 enzyme, CYP2S1, has been identified. It is inducible by dioxin and other classical aryl hydrocarbon receptor ligands. However, little is known regarding the substrates and the functional role of CYP2S1. Since CYP2S1 is predominantly expressed in human lung and trachea, it is reasonable to speculate that CYP2S1 may play an important role in metabolizing the environmental chemicals to which human respiratory tissues are exposed. In the present study, we examined the activity of human CYP2S1 in the metabolism of nicotine and in the activation of three potent carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[a]pyrene (BaP), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The full-length CYP2S1 cDNA was amplified by nested polymerase chain reaction from a human lung cDNA library and was expressed in both Chinese hamster ovary (CHO) cells and Sf9 insect cells. In contrast to the positive controls, i.e., CHO cells expressing human CYP2A13 (for NNK activation) or human CYP1A1 (for BaP activation), there was no increase in NNK- or BaP-induced toxicity in the CHO cells expressing CYP2S1. The heterologously expressed CYP2S1 proteins showed no detectable activity in metabolizing nicotine and PhIP. These results clearly demonstrate that CYP2S1 does not catalyze the metabolism of nicotine and the metabolic activation of these lung carcinogens.
AB - Cytochrome P450 (P450) enzymes play a critical role in the metabolic activation of a wide variety of environmental carcinogens. Recently, a novel human P450 enzyme, CYP2S1, has been identified. It is inducible by dioxin and other classical aryl hydrocarbon receptor ligands. However, little is known regarding the substrates and the functional role of CYP2S1. Since CYP2S1 is predominantly expressed in human lung and trachea, it is reasonable to speculate that CYP2S1 may play an important role in metabolizing the environmental chemicals to which human respiratory tissues are exposed. In the present study, we examined the activity of human CYP2S1 in the metabolism of nicotine and in the activation of three potent carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[a]pyrene (BaP), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The full-length CYP2S1 cDNA was amplified by nested polymerase chain reaction from a human lung cDNA library and was expressed in both Chinese hamster ovary (CHO) cells and Sf9 insect cells. In contrast to the positive controls, i.e., CHO cells expressing human CYP2A13 (for NNK activation) or human CYP1A1 (for BaP activation), there was no increase in NNK- or BaP-induced toxicity in the CHO cells expressing CYP2S1. The heterologously expressed CYP2S1 proteins showed no detectable activity in metabolizing nicotine and PhIP. These results clearly demonstrate that CYP2S1 does not catalyze the metabolism of nicotine and the metabolic activation of these lung carcinogens.
UR - http://www.scopus.com/inward/record.url?scp=14044262238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14044262238&partnerID=8YFLogxK
U2 - https://doi.org/10.1124/dmd.104.002923
DO - https://doi.org/10.1124/dmd.104.002923
M3 - Article
C2 - 15608128
VL - 33
SP - 336
EP - 340
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 3
ER -