Metabolism of NNK in Japanese Americans

STUDY 2: CLINICAL PROTOCOL Metabolism of NNK Among Japanese Americans

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.

Study Overview

• Status: Completed
• Conditions: Smoking
• Intervention / Treatment: Combination product: Modified Natural American Spirit-Tan or Green cigarettes injected with labeled NNK

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.

• Study Type: Observational
• Enrollment (Actual): 16

Contacts and Locations

Study Locations

• United States
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Japanese American Smokers

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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).	Combination product: 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.
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)	Combination product: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	7 days

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: National Cancer Institute (NCI); University of Hawaii
• Investigators: Principal Investigator: Dorothy K Hatsukami, Ph.D, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): October 15, 2021
• Study Completion (Actual): April 14, 2025

Study Registration Dates

• First Submitted: January 9, 2020
• First Submitted That Met QC Criteria: January 13, 2020
• First Posted (Actual): January 14, 2020

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 14, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: CYP2A6, Nicotine Metabolite Ratio, NNAL, NNK α-hydroxylation
• Other Study ID Numbers: 2019NTUC208; P01CA138338 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available in two formats: Summary of the data (graphs and tables) and as raw individual-level data for analysis. Requests for data must be in writing, identify the affiliation and describe how the data will be used. Users agree not to transfer the data to other users and that the data are only to be used for research purposes. The PI will require requestors of data to sign a data and biospecimen sharing agreement that will ensure (1) Use of only for research purposes and not to identify any individual or personal information, (2) Data will be secure, (3) Destruction or return of data after data analysis and (4) Proper citation in publications or other written materials. A record of transfer of data and a copy of the dataset that was distributed will be kept by University of Minnesota.
• IPD Sharing Time Frame: Data will be available after papers are accepted for publication
• IPD Sharing Access Criteria: Data generated by this grant will be made to outside investigators, according to the Guidance at http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No