You Are What You Eat

CH339K

Life Rule 1: Nobody gets out alive

Cover of Science, Sept. 23, 1983

Mutagens and Carcinogens

• Mutagens cause mutations in the DNA genome• Carcinogens increase the cancer rate in a given

organism• Vast majority of carcinogens are mutagens• Not all mutagens are necessarily carcinogenic• Carcinogenesis analysis requires animal studies• Mutagens can be detected more simply and much

less expensively• Restrict carcinogenesis testing to known mutagens

Finding Mutagens – the Ames Test

• Named for Bruce Ames, at UC Berkely• Uses Salmonella typhimurium that has defective histidine anabolism• Strains are used with both point mutations and frameshift mutations in histidine synthesis genes• Rat liver extracts are added to the chemical being studied to mimic bodily metabolism• BECAUSE the actual mutagen may not be the chemical itself, but a metabolic product

Things we put into our food• Cooking your meat over open flame or in a smoker (or using

liquid smoke) produces polyaromatic hydrocarbons (PAHs)

• Cooking your meat over open flame or in a smoker (or using liquid smoke) produces polyaromatic hydrocarbons (PAHs)

• Benzo(A)pyrene is metabolized to benzo[a]pyrene-7,8-diol-9,10-epoxide

Mutagenic action• Benzo(a)pyrene and its

epoxide are intercalators• Intercalating agents stack

between the bases of a DNA double helix

• The epoxide also formas a covalent bond with G residues at N2

• Helix distortion causes copy errors – mostly frameshifts

Heterocyclic amines• Produced in cooked meat and fish from amino

acids, sugars, and creatine

HAs

• mice tumors developed in the liver , forestomach, lung, blood vessels, hematopoietic system, and lymphoid tissue

HAs (cont.)

Heterocyclic amines

“Standard” carcinogens

HAs – Metabolic activation

Natural Pesticides

• Safrole• Aflatoxins• Psoralens• Solanines• Pyrollizidines• Others

Safrole

• Sassafras oil• Banned in USA from foods and skin products• Formerly an ingredient of “natural” root beers• Metabolized to 1-hydroxysafrole• Binds to both DNA and proteins• Induces liver tumors

Aflatoxins

• Produced by Aspergillus molds• Common contaminant of corn, grain, nuts,

peanut butter, bread, cheese, fruit, and apple juice

• Paricularly concentrated in organic peanut butter• Both toxic and carcinogenic

Aflatoxin b1

Aflatoxin Metabolism

Aflatoxin Action

Psoralens

Psoralens are a class of photo-mutagenic and photo-chemotherapeutic molecules that covalently modify nucleic acidsIintercalate into and photoalkylate double stranded DNA. Primary targets of psoralens are thymidine residuesForm both monoadducts and interstrand crosslinksReaction takes place between the 3,4 (pyrone) or 4',5' (furan) double bonds of the psoralen and the 5,6 double bond in pyrimidines .

Psoralens – DNA cross links

Psoralens

• Celery contains up to 100ug/100g• Stressed celery can contain 100x that amount• Celery pickers frequently develop skin rashes

as an occupational hazard• Interestingly, they are also used to treat a

variety of skin diseases

Solanines

15 mg per 200g potatoMost concentrated in green layer under skinCholinesterase inhibitorsTeratogens (cause birth defects)Amounys increase in diseased potatos> 40 mg/200g considered toxic