modulation (Muriel 2007). IFN-α is considered as a hallmark in treating viral

hepatitis, the major cause of liver cirrhosis and hepatocellular cancer all over the

world. IFNs are also known to cause the production of matrix proteins such as

fibronectin and collagen. Muriel et al., demonstrated the effect of IFN-α2b on fibrosis

and cirrhosis induced by CCl4 in rats. Furthermore, there is a recovery of hepatocyte

and erythrocyte membranes to its normal composition as a result of antifibrotic

effects on IFNs (Muriel et al. 1994a; Muriel 1995). A study also demonstrated that

there is downregulation of collagen gene transcription and suppression of CCl4

hepatic fibrosis in mice by IFN-α. Mukai et al., in 2006 showed that IFN-γ prevents

liver fibrosis in nonobese diabetic mice. IFN-α2a causes the reversal of hepatic

cirrhosis induced by thioacetamide in rats (Mathew et al. 2007).

29.2.3 Nitric Oxide

Nitric oxide (NO) gas was investigated as an endogenous vasodilator (Palmer et al.

1987). It is produced from L-arginine by NO synthases, and its synthesis is regulated

by the liver (Muriel 2000). NO helps in regulating the proper functioning of every

organ in the body, and its alteration is involved in various hepatic disorders. NO is

beneficial to maintain the integrity of microvascular function and inhibits the platelet

aggregation and neutrophil infiltration to prevent apoptosis. It also acts as second

messenger in harmful and helpful cytokine signalling. Hence, the modulation of NO

synthesis and NO donors, especially which are liver-specific, can be a powerful tool

in the treatment of liver disorders in future (Muriel 2006).

29.2.4 Sulfoadenosylmethionine (SAM)

SAM is an endogenous molecule which participates in liver health and diseases

(Mato and Lu 2007). The three distinct enzymes that synthesize SAM in mammals

are methionine adenosyltransferase (MAT) I, II and III. The synthesis and utilization

of SAM occur mainly in the liver via MATI, MATIII and glycine N-

methyltransferase, and these three enzymes are responsible for the synthesis and

removal of hepatic SAM (Mato et al. 2002). It has been previously demonstrated that

there is an alteration of methionine metabolism in patients with liver disease. A study

conducted by Kinsell et al. (1948) showed that there is a significant impairment in

the methionine clearance after methionine load in patients having liver disease, and

this suggests the important role of liver in the metabolism of methionine. In most of

transmethylation

reactions,

SAM

is

a

methyl

donor

and

is

utilized

by

methyltransferases in synthesizing various biological compounds including plasma

membrane lipids (Muriel and Mourelle 1992; Muriel 1993). MAT and SAM are

significantly reduced in case of experimental and human hepatic damage (Mato and

Lu 2007). Treatment of animals with SAM showed prevention in the prolonged

biliary obstruction-induced cirrhosis (Muriel et al. 1994b). In another study, the

administration of SAM to alcohol-fed mice, rats and baboons attenuated the

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