Lecture 10 - Carcinogens And Their Targets

Question 1

Cancer

Answer 1

-cell proliferation
-inhibiton of tumor suppressor and apoptosis
-cancer=malignant neoplasm
Associated w/ changes in gene expression
Leading case of death in the world, and canada
What causes cancer? Tobacco 25-40% and obesity
70-90% cancers linked to environment
~200 known chemical carcinogens

Question 2

Carcinogen Classification

Answer 2

Class 1:
-uman and animal
119 chemicals
Asbestos,s soot…(dioxin, benzopyrene0

Class II:
A=81 chemicals

Question 3

Genotoxic Carcinogens

Answer 3

Direct: tumour formation at site of expsure
Ex: ethylene oxide

Indirect: procarcinpgens which require metabolic activation
Ex: benzpyrene

But both interact physically with DNA

Note: the addicts caused by benzypyrene can be complete carcinogens - no theoretical threshold

GENOTOXIC CARCINOEGNS DO NOT HAVE THREHSOLD

Examples: ethylene oxide (direct), Benzypyrene (indirect), DMBA

Direct:
-ethy;ene oxide (1)
-nitrogen mustard (2a)
-methyl methansouflte (2a)
Nischloromethyl ether (1)

Indirect:

• benzyopreyen, benzene; all aromatic hydrocarbons (both class 1)
• aromatic amines (ex: 2-napthylamine)
• nitrosamines
• aflatoxin

Question 4

NON-GENOTOXIC carcinogens

Answer 4

• change gene expression but no physical (binding, damage, or interaction) w/ DNA

Example of a non-genotoxin: DDT dioxin
–> alter geen expresion to induce ROS, inflammation, receptor activation, epogenetic mechanisms

Note: ****NON-GENOTOXIC CHEMICALS ARE NON-MUTAGENIC, HAVE A THRESHOLD, specific (EX: tpa;tissue phorbol wster) is a skin promoter, no activity in liver

Examples: phorbol esters TPA and PMA from cotton plant, ddt dioxin, chloroform (class 2B) 
TCE (class 1 nongenotoxic); chloroform alternative so both non-genotoxic but TCE is more toxic --> contamination in QC due to non-genotixuc TCE  
Ex: PMa CAN ACTIVATE PKC

Question 5

Metabolism of Benzpyrene

Answer 5

-it can be detoxified or toxified (biaoctivation)

Benzopyrene—> detoxified via lung elimination
Benzopyrene —> epoxide –> Bioactivation creates BPDE –> DNA addicts are formed; can either undergo repaie or apoptosis

Question 6

Benzene

Answer 6

-class 1 aromatic hydrocarbon carcinogen; indirect
-inhalation most common
Causes leukaemia
Metabolized by cyp2ei while benzopyrene is 1a1/1b1
Metabolism of Benzene –> hydroquinones, whcih can cause oxidative damage and dna damage by being converted to phenotype radical

Benzene –> HYDROquinones –> phenoxyl radical

Question 7

Aflatoxin

Answer 7

2 mycotoxins from aspergillosis flnghi; aflatoxins are secondary metabolites of fungi
Group 1 carcinogen-most potent naturally occuring carcinogen
Targets the liver (hepatocllular carcinoma) also synergy between hepatitis and aflatoxin; increases chance of liver cancer (hepatellcualr crcinoma x 30)
Aflatoxin can be metabolized by cyp3a4 (liver) and cyp2a13 (lungs_

Question 8

Cyp metabolites

Answer 8

1a1/1b1: benzoypreyen
2e1: benzene
Aflatoxin: 2a1 (lung), 3a4 (liver)

Question 9

TCE

Answer 9

Non-genotoxic carcinogen class 1, axctviated via ppARs (peroxisome proliferator-actviated reveptor)--> TCE chronically actviates this PPAr 
Outbreak in quebec 
Liver and kidney cancer

Question 10

Dioxin

Answer 10

TCDD dioxin is a 2a class carcinogen
NONGENOTOXIC!
Colorless and odourless and not intentionally manufacture 
419 congeners but only 29 toxic (similaer to dioxin)
Toxic effects of dioxin:
Wasting sydnrome
Immune toxicity 
Skin lesionshepatocity cancer
Birth defects

AHR activation by dioxin is ak now mechanism of toxicity 0 just like benzopyrene 
Pure doxion YCDD has been classified as class 1 not bc shown to be toxic to humans but bc