suppresses of liver cancers. Therefore to summarize, chronic

suppresses gene
expression, as 5-methylcytosine interferes with the binding of transcription
factors or other DNA-binding proteins causing reduced transcription. On the
other hand, promoter hypomethylation causes over-expression of associated
genes. Therefore aberrant DNA methylation could be an underlying epigenetic
mechanism that causes altered gene expression that contributes towards the
formation of liver cancers. Therefore to summarize, chronic arsenic exposure
induces hepatic DNA hypomethylation, which can potentially lead to aberrant
gene expression and oncogenic growth in the liver, therefore suggesting a
plausible mechanism of hepatocarcinogenesis.

Estrogens are considered
to be liver carcinogens in rodents and are suspected to cause carcinogenesis in
humans. Evidence suggests that they cause hepatocellular proliferation and
aberrant mitogenesis through ER-mediated mechanisms in addition to the proposal
that they confer epigenetic modifications. Moreover,
arsenic exposure is reported to cause hypomethylation of ER-a promoter region
and ER-a over-expression along with the associated
formation of proliferative lesions and hepatocellular carcinogenesis. Therefore
chronic arsenic exposure causes overexpression of ER-a creating
hypersensitivity of hepatic cells to endogenous steroids.

As evidenced by
microarray analysis, various cell cycle regulating genes like cyclin D1, cyclin
D2, and cyclin D3 were over-expressed by
arsenic. Liver cells that acquired malignant properties upon arsenic treatment
also showed cyclin D1 over-expression. In addition, this over-expression had a
direct effect on the observed malignant transformation as selective cyclin D1 overexpression in the liver was sufficient
enough to initiate hepatocellular carcinogenesis. Cyclin D1 can, therefore, be
considered as a hepatic oncogene.

Cyclin D1 is also known
to be upregulated transcriptionally by various growth factors which potentially
includes estrogens. In estrogen-responsive
tissues like the liver and uterus, proliferative lesions and co-overexpression
of ER-a and cyclin D1 after chronic arsenic exposure is reported. Cyclin D1
activation by arsenic may be a secondary effect to ER-a over-expression as
cyclin D1 is potentially an ER-a-linked gene. Therefore we can expect that
aberrant expression of cyclin D1 along with that of other oncogenes leads to
carcinogenic transformation. Altogether, cyclin D1 overexpression was seen upon
arsenic exposure in multiple in vitro and in vivo model systems of arsenic
carcinogenesis, which includes skin and bladder cancers in rodents.  Thus, under conditions of arsenic-induced carcinogenesis, over-expression
of cyclin D1 is observed consistently.

Glutathione and other
aminothiols such as cysteine and cysteamine comprise the nonprotein sulfhydryls (NPSCs) in a cell and have significant free radical scavenging
abilities. Therefore depletion of intracellular glutathione levels is known have an effect on arsenic mutagenesis.

Studies have shown that
pre-treatment of cells with buthionine sulphoximine (BSO), which inhibits the
biosynthesis of glutathione reduces NPSHs levels in the cell and enhances both
the cytotoxicity and mutagenicity of arsenic. In contrast, glutathione and
cysteine pre-treatment are capable of
protecting mammalian cells against the toxic effects of arsenite.