Dear Ruediger:

The methyl groups of DMBA (7,12-Dimethylbenz[a]anthracene) are not responsible for its potential carcinogenicity. Benzo[a]pyrene, a PAH (polycyclic or polynuclear aromatic hydrocarbon) compound, is one of the most potent rodent carcinogens to have been documented; this molecule possesses no methyl groups. Benzo[a]pyrene and DMBA constitute the most extensively studied PAHs (molecules containing only carbon and hydrogen atoms).

The IARC and USEPA have classified several PAHs as animal carcinogens and some PAH mixtures as carcinogenic to humans.  The EPA classification includes seven PAHs as probable human carcinogens (benzo(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(ah)anthracene, and indeno(1,2,3-cd)pyrene.

Dear Ruediger: 7,12-Dimethylbenz[a]anthracene (DMBA, a polycyclic or polynuclear aromatic hydrocarbon, PAH, containing four fused aromatic rings), comprises an anthracene (containing planar, 3 fused aromatic rings) molecule with an additional angular benzo-ring on top of the anthracene ring, and methyl groups in para-position (at carbons-7 and -12) in the planar anthracene moiety.  In 1961, Charles Huggins and colleagues evaluated DMBA for is carcinogenicity in the mammary gland of rodents; this PAH was considered to be the most carcinogenic of the methylated PAHs assessed. DMBA has been widely employed as a model compound for inducing breast, skin and other cancers in rodents.  DMBA is a procarcinogen, meaning thereby that it needs metabolic activation in mammalian cells in order to generate proximate and ultimate carcinogenic metabolites.  Most of the PAHs are not directly acting genotoxins, and they must be bioactivated to their ultimate carcinogenic forms (diol epoxides), which form adducts with DNA, thus causing genotoxic damage.

Cytochrome P450-dependent mammalian enzymes mediate the bioactivation of DMBA in rodent cancer cells. Two such microsomal mixed-function oxygenases catalyze the generation of the ultimate carcinogen of DMBA, DMBA-3,4-dihydrodiol-1,2-epoxide. This electrophilic intermediate binds to nucleophilic centers in DNA (generating carcinogen-DNA adducts), to initiate mutagenicity. The methyl groups of DMBA are metabolized to hydroxy-methyl derivatives. However, these are not responsible for carcinogenicity (as was considered 2 or 3 decades ago).

Dear Prof. Chithan,

thank you for that precise explanation.

Kind regards

Dear Dr. Richter,

Thank you! I must say that your question is a very interesting one, and I appreciate it. The potential effects of the methyl groups of DMBA, an organ specific procarcinogen, can be intriguing and profound. The ultimate carcinogenic form of DMBA (the diol epoxide) is generated from the "bay" (in the anthracene moiety) region of the molecule. Methyl substitutions in the molecule adjacent to the bay (the angular benzo-ring, which forms a bay shape) region seem to increase potential carcinogenic activity. However, the methyl groups in the 7- and 12- positions are not in the vicinity of the bay region, and yet DMBA is tremendously active in initiating carcinogenesis.

The role of estrogens (and estrogen receptors, and hormonal status) in DMBA induced carcinogenesis is also fascinating. Incidentally, beta-estradiol molecule shares structural similarities (particularly shape) with DMBA.

Here are some links pertaining to the methyl groups of DMBA (and their potential effects) and methylchrysenes, which may be of interest.

http://www.ncbi.nlm.nih.gov/pubmed/?term=7%2C12-DMBA+is+more+carcinogenic

 http://www.ncbi.nlm.nih.gov/pubmed/3891118

 http://www.ncbi.nlm.nih.gov/pubmed/3652037

Kind regards. 

The answer is made clear is our comprehensive review entitled, Structure, function and carcinogenicity of metabolites of methylated and non-methylated polycylic aromatic hydrocarbons by James W. Flesher and Andreas F. Lehner (2016)@ L. F .Fieser and his group at Harvard provided necessary foundation and MJS Dewar showed us how to calculate the location of the most reactive centers for substitution in the molecular

Dear Dr. Flesher,

thank you for your competent input. Unfortunately the answer was uploaded incomplete, only. I would appreciate if you could update the text, accordingly.

kind regards

Ruediger B. Richter

I have attempted to answer the question several times but my answer suddently disappears from view. In 1968, Dipple et al proposed that the appearance of carcinogenic activity in polycyclic aromatic hydrocarbons depends on the structure of the ultimate carcinogen rather than the structure of the parent hydrocarbon. For methylated hydrocarbons the proximate carcinogens were hydroxymethy metabolites and the ultimate carcinogens were their sulfate esters capable of generating reactive species of molecular structure type ArCH2+. When unsubsttuted hydrocarbons undergo ring oxidatiion they form detoxified compounds with structure type ArX. It is obvious that these two different structure types are mutually exclusive because they cannot function as ultimate carcinogens in the same manner. So how can usubstituted hydrocarbons produce cancer ? By undergoing bioalkylation (methylation) at the most reactive center in the molecule. Thus beno[a]pyrene is converted by cytosolic SAM-dependent methytransferase to 6-methybenzo[a]pyrene in the first step of the metabolic activation of benzo[a]pyrene. No theory relating ring oxdidation products with molecular structure type ArX can account for the fact that substitution of unsubstituted hydrocarbons with hydroxy or acetoxy groups at the reative meso-positons will abolish the production of cancer.

No theory relating ring oxidation products with molecular structure type ArX to carcinogenic activity, can account for the fact that substitution of unsubstituted hydrocarbons with hydroxy or acetoxy groups at the reactive meso-positons will abolish the production of cancer.

What question or comment do readers have about the specific predictions of our Unified Theory ? What experiment or several of them could disprove the specific predictions of the Unified Theory ?

How much impact did the paper entitled, "Bioalkylation of benz[a]anthracene as a biochemical probe for carcinogenic activity: Lack of bioalkylation in a series of six Non-carcinogenic Polynuclear Aromatic Hydrocarbons" by J.W. Flesher and S. R. Myers have on establishing the validity and generality of the Unified Theory ? The paper was published in Drug Metabolism and Disposiiton Vol 18, no 2, p 163 (1990)

The answer to the question of the role of meso-methyl substitution in the metabolic activation of unsubstuted hydrocarbons is explained in Review Journal of Chemistry 2019 v9 no 4 pp 197-254 by James 'w. Flesher and Andreas F. Lehner. "The Structural Basis for the Production of Cancer and Detoification by Oxidized Metabolites of Meso-Anthracenic Methylated and Non-Methylated Polynulear Hydrocarbons: A Paradigm Shift

Theories of PAH carcinogensis that do not cite the fundamental contributions in the papers published by Fieser et all do not have a fighting chance that their alternative theory is correct,