S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells

Abstract

S-adenosylmethionine (AdoMet) is an essential compound in cellular transmethylation reactions and a precursor of polyamine and glutathione synthesis in the liver. In liver injury, the synthesis of AdoMet is impaired and its availability limited. AdoMet administration attenuates experimental liver damage, improves survival of alcoholic patients with cirrhosis, and prevents experimental hepatocarcinogenesis. Apoptosis contributes to different liver injuries, many of which are protected by AdoMet. The mechanism of AdoMet's hepatoprotective and chemopreventive effects are largely unknown. The effect of AdoMet on okadaic acid (OA)-induced apoptosis was evaluated using primary cultures of rat hepatocytes and human hepatoma cell lines. AdoMet protected rat hepatocytes from OA-induced apoptosis dose dependently. It attenuated mitochondrial cytochrome c release, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. These effects were independent from AdoMet-dependent glutathione synthesis, and mimicked by 5-methylthioadenosine (MTA), which is derived from AdoMet. Interestingly, AdoMet and MTA did not protect HuH7 cells from OA-induced apoptosis; conversely both compounds behaved as proapoptotic agents. AdoMet's proapoptotic effect was dose dependent and observed also in HepG2 cells. In conclusion, AdoMet exerts opposing effects on apoptosis in normal versus transformed hepatocytes that could be mediated through its conversion to MTA. These effects may participate in the hepatoprotective and chemopreventive properties of this safe and welltolerated drug. (HEPATOLOGY 2002;35:274-280.)

Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

“…Regarding TGM2, its elevation upon MTA accumulation correlates with the restricted doxorubicin-induced apoptotic response, as also reported in other studies (71) and with NFB activation likely mediated by its kinase activity (72). In contrast with our results, there are studies reporting the proapoptotic and antiproliferative effects induced in hepatoma cells upon exposure to pharmacological concentrations of MTA (27). This apparent discrepancy might be reconciled assuming that the MTA concentration used in other investigations is much higher than the physiological/pathological levels reported in this study.…”

“…4-methylthio-2-oxobutanoic acid is finally converted into methionine, completing the methionine salvage pathway that recycles back MTA into the one carbon metabolism to promote SAMe synthesis and therefore contribute to the maintenance of the methylation capacity of the cell. Modification of MTA levels has been associated with regulation of cell proliferation (26), apoptosis (27), and inflammatory reactions (19). However, the underlying mechanisms are still only partially understood and besides other regulatory systems, it may involve the control of protein methylation reactions.…”

Role of S‐adenosyl‐L‐methionine in liver health and injury†

“…Although SAMe protected against okadaic acid-induced apoptosis in normal hepatocytes, it induced apoptosis in liver cancer cell lines HepG2 and HuH-7 via the mitochondrial death pathway. 39 MTA also recapitulated these actions. MTA can be derived from SAMe enzymatically and non-enzymatically.…”

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

“…Thus, although both mutants likely affect the function of APIP in methionine salvage, we suspect that H115A is also affecting protein conformation or stability in a way that renders APIP unable to inhibit cysteineaspartic protease 9 (CASP9)-mediated cell death. Others have reported that MTA can both inhibit and increase apoptosis depending on the cell type (50,51). Published studies showing APIP inhibition through binding to APAF-1 (31) and regulation of protein phosphorylation (36) provide alternative mechanisms where APIP could regulate apoptosis independent of its role in methionine salvage.…”