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) 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 acids Iintercalate into and photoalkylate double stranded DNA. Primary targets of psoralens are thymidine residues Form both monoadducts and interstrand crosslinks Reaction 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 potato Most concentrated in green layer under skin Cholinesterase inhibitors Teratogens (cause birth defects) Amounys increase in diseased potatos > 40 mg/200g considered toxic