Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human peripheral lung microsomes.
The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.9%/mg protein/min. Based on total bioactivation of NNK and NNAL by alpha-carbon hydroxylation, subjects could be classified as either high (17 subjects) or low (12 subjects) bioactivators [(5.26 +/- 1.23) x 10(-2) and (6.49 +/- 5.90) x 10(-3)% total alpha-hydroxylation/mg protein/min, P < 0.05]. Similarly, for detoxification, subjects could be grouped into high (9 subjects) and low (20 subjects) categories [(2.03 +/- 1.65) x 10(-3) and (2.50 +/- 3.04) x 10(-4)% total N-oxidation/mg protein/min, P < 0.05]. When examining data from all individuals, no significant correlations were found between levels of CYP2A mRNA, CYP2A enzyme activity, or CYP2A immunoinhibition and the degree of total NNK bioactivation or detoxification (P > 0.05). However, subgroups of individuals were identified for whom CYP2A13 mRNA correlated with total NNK and NNAL alpha-hydroxylation and NNAL-N-oxide formation (P < 0.05). The degree of NNAL formation and CYP2A13 mRNA was also correlated (P < 0.05). Subjects (n = 84) were genotyped for the CYP2A13 Arg257Cys polymorphism, and NNK metabolism for the one variant (Arg/Cys) was similar to that for other subjects. Although results do not support CYP2A13 or CYP2A6 as predominant contributors to NNK bioactivation and detoxification in peripheral lung of all individuals, CYP2A13 may be important in some.
Brown
Pamela J
PJ
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Bedard
Leanne L
LL
Reid
Ken R
KR
Petsikas
Dimitri
D
Massey
Thomas E
TE
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006018:Glycols / Q000378:metabolism; D006801:Humans; D006880:Hydroxy Acids / Q000378:metabolism; D006900:Hydroxylation; D007651:Keto Acids / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology* / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009602:Nitrosamines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D012907:Smoking / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
D006018:Glycols; D006880:Hydroxy Acids; D007651:Keto Acids; D009602:Nitrosamines; D011725:Pyridines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C029009:steroid hormone 7-alpha-hydroxylase; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol