Relationship of Urinary Mercapturic Acids of Selected Tobacco Smoke Constituents to Chronic Obstructive Pulmonary Disease in Cigarette Smokers of the Singapore Chinese Health Study

α,β-Unsaturated carbonyl compounds in cigarette smoke, such as acrolein and acrylamide, are considered as possible causative factors for chronic obstructive pulmonary disease (COPD) in people who smoke cigarettes. A major route of metabolism of these compounds is reaction with glutathione to form adducts that are further metabolized and excreted in the urine as mercapturic acids, which serve as useful dosimeters of exposure. In this study, we analyzed urine samples from the Singapore Chinese Health Study, a prospective epidemiology study of 63,257 men and women 45-74 years old with Chinese origin who were permanent residents or citizens of Singapore when they were enrolled in 1993-1998. A case-control study with 100 incident cases of COPD and 100 matched controls, all of whom were current cigarette smokers, was conducted within this cohort. Urine samples of the study subjects were collected during follow-up I (2000-2005) and the COPD cases were identified in follow-up II interviews (2006-2010). Urinary mercapturic acids of acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA, <b>1</b>), acrylamide (2-carbamoylethyl mercapturic acid, 2-CaEMA, <b>2</b>), acrylonitrile (2-cyanoethyl mercapturic acid, 2-CyEMA, <b>3</b>), crotonaldehyde (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA-1, <b>4</b>), methacrolein (3-hydroxy-2-methylpropyl mercapturic acid, HMPMA-2, <b>5</b>), and methyl vinyl ketone (3-hydroxy-3-methylpropyl mercapturic acid, HMPMA-3, <b>6</b>) were quantified using a LC-MS/MS method. Urinary levels of 2-CaEMA, the mercapturic acid of acrylamide, were significantly higher in cases (geometric mean 361.0 pmol/mg creatinine) than in controls (293.7 pmol/mg creatinine) and the increasing level of 2-CaEMA in tertiles was significantly associated with increased odds of developing COPD (both <i>P</i> <0.05), after adjustment for cigarettes per day and years of cigarette smoking. For the mercapturic acid of acrylonitrile, a weak trend of increasing 2-CyEMA with the COPD status was observed (<i>p</i> trend = 0.033), while none of the other mercapturic acids were significantly related to the risk of COPD. These results indicate that acrylamide in cigarette smoke should be given strong consideration as a cause of COPD in people who smoke.