THE LIVER AS A CENTRAL REGULATOR OF HYDROGEN SULFIDE

The liver is likely exposed to high levels of hydrogen sulfide (H2S) from endogenous hepatic synthesis and exogenous sources from the gastrointestinal tract. Little is known about the consequence of H2S exposure on the liver or hepatic regulation of H2S levels. We hypothesized that the liver has a high capacity to metabolize H2S and that H2S oxidation is decreased during sepsis, a condition in which hepatic O-2 is limited and H2S synthesis is increased. Using a nonrecirculating isolated and perfused liver system, we demonstrated rapid hepatic H2S metabolism up to an infusion concentration of 200' mu M H2S. Hydrogen sulfide metabolism was associated with an increase in O-2 consumption from a baseline 96.7 +/- 7.6 mu mol O-2/min/kg to 109 +/- 7.4 mu mol O-2/min/kg at an infusion concentration of 150 mu M H2S (P < 0.001). Removal of O-2 from the perfusate decreased H2S clearance from a maximal 97% to only 23%. Livers isolated from rats subjected to cecal ligation and puncture (CLP) did not differ significantly from control livers in their capacity to metabolize H2S, suggesting that H2S oxidation remains a priority during sepsis. To test whether H2S induces O-2 consumption in vivo, intravital microscopy was utilized to monitor the oxygen content in the hepatic microenvironment. Infusion of H2S increased the NADH/NAD(+) ratio (645 gray-scale-unit increase, P = 0.035) and decreased hepatic O-2 availability visualized with Ru(Phen)(3)(2+) (439 gray-scale-unit increase, P = 0.040). We conclude that the liver has a high hepatic capacity for H2S metabolism. Moreover, H2S oxidation consumes available oxygen and may exacerbate the tissue hypoxia associated with sepsis.