TABLE 4.

Potential Mechanisms for Arsenic Hepatocarcinogenesis

Mechanisms	Outcomes	Representative reference
Oxidative damage
Oxidative stress	Lipid peroxidation, GST-pi positive foci	Mazumder, 2005; Nishikawa et al., 2002
Oxidative-related gene expression	Induction of HO-1, MT, and GSH-related enzymes	Liu et al., 2001b, 2006a
Oxidative DNA damage	Increase in hepatic DNA 8-OHdG levels	Kinoshita et al., 2007; Shen et al., 2003
Altered DNA repair
Impaired repair of DNA damage		Inhibition of NER and BER
Interact with zinc finger proteins	Interfere with PARP-1, Fgp, XPA, etc	Andrew et al., 2006; Hartwig et al., 2003
Apoptotic tolerance and cell proliferation
Apoptosis tolerance	Apoptosis tolerance for damaged cells to survive	Qu et al., 2002
Enhanced cell proliferation	Proliferative lesions, cyclin D1, PCNA expression	Waalkes et al., 2000
DNA methylation and genomic instability
Hypomethylation	Liver global and ER-α hypomethylation	Waalkes et al., 2004a; Zhao et al., 1997
	Chromosomal instability	Sciandrello et al., 2004
	DNMTs and Ha-ras gene suppression	Okoji et al., 2002; Reichard et al., 2007
Hypermethylation	Hypermethylation of p16	Liu et al., 2006a
	Hypermethylation of p53	Mass and Wang, 1997
Aberrant estrogen signaling
ER-α overexpression	Intense staining of ER-α in arsenic induced tumors	Waalkes et al., 2004a, 2006b
Estrogen linked gene expression	ER linked gene expression in adult and fetal livers	Liu et al., 2004, 2006b
Altered steroid metabolism	Altered steroid metabolism and liver feminization	Liu et al., 2007
Synergistic effects with DES	Increased liver tumors following postnatal DES	Waalkes et al., 2006a, b

Note. The details of the experimental systems are described in the text. HO-1, heme oxygenase-1; MT, metallothionein; DNMT, DNA methyltransferase; DES, diethylstilbestrol.