he fact that gases could act as messengers in our bodies to mediate, among other things, blood flow when needed was unthinkable as late as the 1980s. At present it is well established that nitric oxide, an environmental pollutant, serves as a gaseous mediator, or "gasomediator," in our bodies. As a biological-messenger molecule, its involvement reveals itself in diverse biological processes such as vasodilatation, inflammatory processes, and neurotransmission. Doctors can now treat premature babies with persistent pulmonary hypertension (blood vessels in the lungs fail to relax and allow blood flow) by giving them nitric oxide inhalation therapy. Understanding how nitric oxide works - its vasodilating action in the penis - has made Viagra a runaway success, and research continues into this gas and its surprising effects on other parts of the human body, including the brain. (See INNOVATION, Vol 3 No 2, 2002, page 58.)

To say hydrogen sulphide, a toxic gas, plays a physiological role in our body is a case of déjà vu. Hydrogen sulphide, until recently a relatively unstudied gasomediator, is a colourless, flammable gas with a distinctive rotten-egg odour. Its concentration in the air is very low, between 0.03 and 0.1 microgram per cubic metre (µg/m³). Found naturally in crude petroleum, natural gas, volcanic gases, and hot springs, the gas is also produced by bacteria. As a by-product of pulp and paper manufacturing and as an agricultural disinfectant, hydrogen sulphide kills 30 or so people each year in the United States because of its toxicity from related industries. The toxicity of the gas results from its reaction with cytochrome oxidase, an enzyme in mitochondria. Mitochondria, the powerhouses of cells, generate energy from food and oxygen for the body. When hydrogen sulphide inhibits cytochrome oxidase, oxygen becomes unavailable to the mitochondria, resulting in reduction of energy generation and eventual death.

However, even though our noses detect hydrogen sulphide in the air at 8µg/m³, toxicity occurs at much higher levels. Evidence exists that liver mitochondria function normally in hydrogen sulphide concentrations of 50 micromolar (µM) or more, and one recent study has even shown that chicken-liver mitochondria can use hydrogen sulphide to manufacture energy. Mammalian cells produce the gas. Human blood contains between 10 and 100µM of the gas, and 100-150µM in the brain.

Observation of the brains of patients with Alzheimer's disease shows that lower hydrogen sulphide levels imply a possible pathophysiological role for this novel mediator. Researchers suggest that hydrogen sulphide in the brain may have a role in memory formation.

With extensive research experience on nitric oxide at King's College, London, and having been involved in the discovery of new classes of enzyme inhibitors for nitric oxide, Philip Moore, head of the Department of Pharmacology, National University of Singapore, has taken a special interest in the novel hydrogen sulphide molecule. "Apart from published research carried out in Japan and Canada, there has been relatively little work done elsewhere on hydrogen sulphide as a gasomediator," he explains.

Mammalian cells synthesise hydrogen sulphide from cysteine, the sulphydryl-containing amino acid, by the action of two enzymes: cystathionine-gamma-lyase (CSE) and cystathioninebeta-synthetase (CBS). Not surprisingly, both smooth muscle and the brain contain these enzymes. However, because the two occur in varying amounts in various tissues, the possibility exists that these enzymes have different roles. CSE levels are high in the smooth muscles of blood vessels of the lungs and heart besides being detectable in the brain, liver, and kidney whereas CBS is undetectable in blood vessels but found in the brain, specifically the hippocampus, cortex, brainstem and cerebellum. The hippocampus plays important roles in normal memory and information processing in humans.

Working with physiologically relevant concentrations such as those present in cells and making use of a range of inhibitors to the enzymes CSE and CBS, Moore and his team found they could demonstrate a range of biological effects. "Hydrogen sulphide relaxes smooth muscle in blood vessels and organs; it is a powerful vasodilator and, perhaps working in concert with nitric oxide, influences blood pressure and blood supply to organs," Moore says. Research publications are currently in progress.

"Hydrogen sulphide may also affect microvascular perfusion (blood supply) and leakage and as such could play a part in mechanisms underlying inflammatory disease," he continues. A study recently published in the Journal of Infection reported increased formation of hydrogen sulphide following septic shock (a serious condition that occurs when an overwhelming infection leads to a dramatic fall in blood pressure).

Could hydrogen sulphide serve as a novel target for new antiinflammatory drugs for the treatment of arthritis and septic shock? Will its therapeutic applications equal or better nitric oxide one day?

Moore notes: "Relying on information gathered to date, I believe hydrogen sulphide is likely to be a 'mediator to watch' in years to come. What we know at this moment about hydrogen sulphide is just the start; more work needs to be done to gain an understanding of its biological significance in health and disease - the mechanisms involved in the biosynthesis, breakdown, and action of the gas."

Some fundamental differences may exist in the substrate and enzyme required for production of hydrogen sulphide and nitric oxide (the enzyme nitric oxide synthase manufactures nitric oxide from arginine). An interaction may take place between gases in the gasomediator family - another area in which the professor takes an interest. Besides nitric oxide, the family of gasomediators includes carbon monoxide, hydrogen sulphide, and possibly others.

Encouraged by the push for biomedical research in Singapore, Moore has set long-term research goals encompassing therapeutic applications. "We would be looking to collaborate with various bodies - pharmaceutical companies, for example," he says. "As the population ages, having a fundamental understanding of the possible roles of hydrogen sulphide in such areas as cardiovascular disease and rheumatoid arthritis, and the effects of relevant therapeutic agents, will have great value."

For more information contact Philip Moore at phchead@nus.edu.sg

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