Cigarette

• • > 7000 chemicals in cigarette smoke
  • > 70 linked to cancer (not only lung cancer)
• Most carcinogens in cigs need metabolic activation (= Procarcinogens)

  • Generally catalyzed by cytochrome p450 enzymes
• 1. Benzo[a]pyrene cross cell membrane
  2. AhR in complex with HSP40
  3. PAH bind AhR
  4. HSP40 released from AhR
  5. PAH + AhR translocate to nucleus; interact with ARNT
  6. PAH + AhR + ARNT bind to transcription regulatory region --> promote transcription of CYP1A1 & CYP1B1 --> activate pro-carcinogens
• CYP1A1 and CYP1B1: inducible by cigs through interaction with acyl hydrocarbon receptor (AhR)
• AhR: also mediates toxicological process from environmental contaminants (e.g. TCDD, Photoproducts) generated after radiation exposure
• • Activation of procarcinogens by CYP450 --> Carcinogen
  • Metabolic detoxification: GST, UGT, Epoxide hydrolase, Sulfatase
• Polymorphisms (Genetic variants) in these enzymes = higher activation & lower detoxification = highest risk for smoking related cancers
• Measurements of carcinogens/ their metabolites in urine, blood, breath: provide quantitative info (Biomarkers) on human exposure to them