Smoking
Conditions
Keywords
CYP2A6, Nicotine Metabolite Ratio, NNAL, NNK α-hydroxylation
Brief summary
The risk of lung cancer varies by individual and by ethnic/racial group. In this study the investigators will explore how individual differences in the metabolism of a tobacco-specific lung carcinogen may contribute to the variable risk of lung cancer between ethnic/racial groups. In this 10 day clinical trial, Japanese Americans will smoke a cigarette containing deuterium-labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen. The study cigarette will be smoked for 7 days. This will allow for NNK metabolic profiling and determining the effect of CYP2A6 genotype on the level of NNK α-hydroxylation in Japanese Americans smokers using \[pyridine- D4\]-NNK containing cigarettes.
Detailed description
Eligible subjects will provide a baseline 24 hour urine sample. Study cigarettes spiked with labeled NNK will be provided to the subjects to smoke over a 7 day period. During this time, 24 hour urine samples will be collected over days 5, 6 and 7 on study cigarettes. Blood will be drawn on days 6 and 7 on study cigarettes. Samples will be analyzed for NNK metabolism.
Interventions
COMBINATION_PRODUCTModified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK
American Spirit cigarettes will be modified by adding 0.300 μg \[pyridine-D4\]NNK to each cigarette so that the amount of total (deuterated plus unlabeled) NNK in these cigarettes is below 0.700 μg/g tobacco.
Sponsors
University of Hawaii
National Cancer Institute (NCI)
Masonic Cancer Center, University of Minnesota
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Japanese American - one, but preferably 2 biological parents of Japanese descent 2. 21 years or older 3. Daily smoker 4. Eligible urinary ratios of total 3-hydroxycotinine to cotinine (3HC/COT): * Little or no-CYP2A6 activity defined as a 3-hydroxycotinine:cotinine ratio of \<0.6 or * Relatively high CYP2A6 activity defined as a 3-hydroxycotinine:cotinine ratio of \>3.0. 5. Stable and good physical and mental health 6. Provided written informed consent to participate in the study
Exclusion criteria
1. Unwilling to avoid other nicotine containing products during the study and no use of any nicotine-containing products except cigarettes for 1 week prior to their study visits 2. Currently taking any medications that affect relevant metabolic enzymes 3. Experiencing medical conditions that might affect biomarkers of exposure and effect 4. Pregnant or nursing or planning on becoming pregnant during the study 5. Unable to read and understand English
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Ratio of D4-hydroxy Acid to D4- NNAL (an Estimate if NNK Alpha Hydroxylation) | 7 days | Difference in means of the ratio of D4-hydroxy acid to D4- NNAL (an estimate if NNK alpha hydroxylation) for the two groups (null versus average CYP2A6 activity) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Smokers With Very Low or no CYP2A6 Activity Japanese American smokers (daily \> 5 cigarettes) with little or no CYP2A6 activity (CYP2A6 activity defined as a ratio of trans-3-hydroxycotinine:cotinine ratio of \<0.6).
Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK: American Spirit cigarettes will be modified by adding 0.300 μg \[pyridine-D4\]NNK to each cigarette so that the amount of total (deuterated plus unlabeled) NNK in these cigarettes is below 0.700 μg/g tobacco. | 8 |
| Smokers With High CYP2A6 Activity Japanese American smokers (daily \> 5 cigarettes) with high CYP2A6 activity (CYP2A6 activity defined as a ratio of trans-3-hydroxycotinine:cotinine ratio of \> 3.0)
Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK: American Spirit cigarettes will be modified by adding 0.300 μg \[pyridine-D4\]NNK to each cigarette so that the amount of total (deuterated plus unlabeled) NNK in these cigarettes is below 0.700 μg/g tobacco. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Smokers With Very Low or no CYP2A6 Activity | Smokers With High CYP2A6 Activity | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
The Ratio of D4-hydroxy Acid to D4- NNAL (an Estimate if NNK Alpha Hydroxylation)
Difference in means of the ratio of D4-hydroxy acid to D4- NNAL (an estimate if NNK alpha hydroxylation) for the two groups (null versus average CYP2A6 activity)
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Smokers With Very Low or no CYP2A6 Activity | The Ratio of D4-hydroxy Acid to D4- NNAL (an Estimate if NNK Alpha Hydroxylation) | 0.133 Ratio | Standard Deviation 0.096 |
| Smokers With High CYP2A6 Activity | The Ratio of D4-hydroxy Acid to D4- NNAL (an Estimate if NNK Alpha Hydroxylation) | 0.175 Ratio | Standard Deviation 0.066 |