benzo[a]pyrene

Benzo[a]pyrene, C20H12, is a five-ring polycyclic aromatic hydrocarbon that is mutagenic and highly carcinogenic. It is a crystalline yellow solid.

Benzo[a]pyrene is a product of incomplete combustion at temperatures between 300 and 600°C. Is found in coal tar, in automobile exhaust fumes (especially from diesel engines), tobacco smoke, and in charbroiled food.

Recent studies have revealed that levels of benzopyrene in burnt toast are significantly higher than once thought, although it is unproven whether burnt toast is itself carcinogenic.

DNA interactions

Benzo[a]pyrene diol epoxide ((+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) (BPDE) is the carcinogenic product of three enzymatic reactions.

Benzo[a]pyrene is first activated by cytochrome P4501A1 to form (+)-benzo[a]pyrene 7,8-oxide among other products. Next, (+)-benzo[a]pyrene 7,8-oxide is metabolized by epoxide hydrolase to yield (-)-benzo[a]pyrene-7,8,dihydrodiol.

(-)-benzo[a]pyrene-7,8,dihydrodiol forms the ultimate carcinogen after reacting with cytochrome P4501A1 to yield benzopyrene diol epoxide ((+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene).

The two carbons of the epoxide are electrophillic, due to an unequal sharing of electrons with the oxygen. As a result, this molecule intercalates in DNA, covalently bonding to the nucleophillic guanine nucleobases at the N2 position.

A recent X-ray crystallography study shows this distorts the DNA. This can disrupt the normal process of copying DNA, and may lead to cancer. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.

Benzo[a]pyrene induces high concentrations of cytochrome P4501A1 (CYP1A1) by binding to the AhR (aromatic hydrocarbon receptor) in the cytosol.

Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon nuclear traslocator) and then binds xenobiotic response elements (XREs) in DNA located upstream of certain genes.

This process increases transcription of certain genes, notably CYP1A1, followed by increased CYP1A1 protein production. This process is similar to induction of CYP1A1 by certain polychlorinated biphenyls and dioxins.

See also

 carcinogens
 BPDE