There are currently five different organizations that have methods of classifying carcinogens.  None of the organizations, either nationally or internationally, consider PhIP to be safe.  This justifies the need to decrease these chemicals in our diet.  Although some research has shown that antioxidants will decrease HCA formation, there was little evidence as tho why this occurs, or if pH was a mitigating factor.

Amines are organic compounds in which one or more of the hydrogen atoms in ammonia, NH3, are replaced with an alkyl group (alkane chain) or aryl group (aromatic ring).  In most heterocyclic amines, a five- or six-atom ring contains one or more nitrogen atoms.  There are numerous heterocyclic amines that are present in grilled chicken, but one of the most prevalent and potent is phenylimidazopyridine (PhIP); it has the chemical formula C13H12N4

Although the exact pathway of heterocyclic amine formation is not known, it is believed to transpire during the Maillard reaction.  The Maillard reaction is a complicated series of reactions that cause non-enzymatic browning.  This complex set of reactions between amines (usually from proteins) and carbonyl compounds (usually from sugars) have many consequences.  Some of these consequences are desirable, such as improved color, flavor, and increase in antioxidants.  Other consequences are negative, such as impacting food quality during storage, loss of nutritional value, and an increase in mutagenicity.  The Maillard reaction can be summarized in five steps: condensation, rearrangement, fragmentation, Strecker degradation, and polymerization.

The initial step, condensation, is the reaction between a reducing sugar and a primary amino acid.


The initial step of the Maillard reaction between glucose and an amino acid (H2N-R), in which R is the amino acid side group.


            After the formation of N glycoside under acid catalysis an immonium ion forms and then isomerizes.  This reaction is called Amadori rearrangement and forms a compound called a ketosamine:


The ketosamine products then undergo the third step in the Maillard reaction, fragmentation.   The glycosylamines and Amadori products are intermediate products of the Maillard reaction, the concentration depending on factors such as pH, temperature in which the reaction occurs, and time it takes for the reaction to occur.  The Amadori products then undergo degradation to form deoxyosones in an environment with a pH of 4-7.  The deoxyosones formed react and form secondary products.

The next step in the Maillard reaction is the Strecker reaction.  This reaction involves a reaction between the deoxyosones and amines.  The reaction yields aminoketones and aldehydes, which are responsible for the strong odors produced, and carbon dioxide during the process of transamination.  The condensation of the aminoketones yields pyrazine derivatives (aromatic compounds).  Pyrazine is another family of heterocyclic amines. 

The final step in the Maillard reaction is polymerization.  Polymerization is a process during which brown nitrogen pigments are formed by aldol condensation and carbonyl polymerization.  Polymerization forms long chains of atoms that are sometimes poorly defined.  A series of condensations and water eliminations forms the heterocycles.

According to the Nurses’ Health Study, the daily food consumption of chicken is 21.2±21.4 g and the PhIP consumed is 204.0±370.0 ng/day.  The ingested levels meet or exceed the levels given in the cancer studies.  Many studies have consistently shown that PhIP causes mutations in most test systems such as prokaryotes, rodents exposed in vivo, and cultured rodent and human cells.  In addition to showing a high degree of potency, these specific heterocyclic amines also cause sister chromatid exchange, micronucleus formation (a sign of chromosome damage or loss), and unscheduled DNA synthesis (a DNA repair response).  As mutagens, HCAs can form mutations in the DNA by bonding to the DNA and causing it to duplicate improperly and mutate unchecked—the first step in cancer development.  A mutagen is any agent (physical or environmental) that can induce a genetic mutation or can increase the rate of mutation.  Most of these HCAs also induced DNA damage and chromosomal aberrations (changes in chromosome structure or number) in in vivo studies in rodents and in in vitro human and rodent cell studies (IARC 1993, NTP 2002).