Benzo(a)pyrene - Interaction With DNA

Interaction With DNA

Properly speaking, benzopyrene is a procarcinogen, meaning that the mechanism of carcinogenesis of benzopyrene depends on enzymatic metabolism of benzopyrene to the ultimate mutagen, benzopyrene diol epoxide, pictured above at right. This molecule intercalates in DNA, covalently bonding to the nucleophilic guanine nucleobases at the N2 position. X-ray crystallographic and nuclear magnetic resonance structure studies show that this binding distorts the DNA, inducing mutations by perturbing the double-helical DNA structure. This disrupts the normal process of copying DNA and induces mutations, which explains the occurrence of cancer after exposure. This mechanism of action is similar to that of aflatoxin which binds to the N7 position of guanine.

There are indications that benzopyrene diol epoxide specifically targets the protective p53 gene. This gene is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. By inducing G (guanine) to T (thymidine) transversions in transversion hotspots within p53, there is a probability that benzopyrene diol epoxide inactivates the tumor suppression ability in certain cells, leading to cancer.

Benzopyrene-7,8-dihydrodiol-9,10-epoxide is the carcinogenic product of three enzymatic reactions:

  1. Benzopyrene is first oxidized by cytochrome P4501A1 to form a variety of products, including (+)benzopyrene-7,8-epoxide.
  2. This product is metabolized by epoxide hydrolase, opening up the epoxide ring to yield (-)benzopyrene-7,8-dihydrodiol.
  3. The ultimate carcinogen is formed after another reaction with cytochrome P4501A1 to yield the (+)benzopyrene-7,8-dihydrodiol-9,10-epoxide. It is this diol epoxide that covalently binds to DNA.

Benzopyrene induces cytochrome P4501A1 (CYP1A1) by binding to the AHR (aryl hydrocarbon receptor) in the cytosol. Upon binding the transformed receptor translocates to the nucleus where it dimerises with ARNT (aryl hydrocarbon receptor nuclear translocator) 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. Seemingly, CYP1A1 activity in the intestinal mucosa prevents major amounts of ingested benzo(a)pyrene to enter portal blood and systemic circulation. Intestinal, but not hepatic, expression of CYP1A1 depends on TOLL-like receptor 2 (TLR2), which is a eucaryotic receptor for bacterial surface structures such as lipoteichoic acid.

Moreover, benzopyrene has been found to activate a transposon, LINE1, in humans.

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