Genes that harm Genes that heal

Genes do more than predict the colour of your eyes. They also contain valuable information about your susceptibility to certain diseases.

Genes are fascinating stuff. Not only do they cause some people to have curly hair while others have straight tresses, they also regulate various other bodily functions.

Dr Cedric Werely of the MRC/US Centre for Molecular
and Cellular Biology examines a model of a DNA molecule.
Picture: Allen Jefthas. Courtesy of the MTN Science Centre.

Dr Cedric Werely from the MRC/US Centre for Molecular and Cellular Biology says any living organism is constantly under chemical attack - whether it's from the medicines we take or substances in the environment. To ward off these attacks and render any potentially cancer causing chemicals harmless, our bodies have a variety of drug metabolizing enzymes (DMEs).

However, people differ in the way they react to chemicals. Some people might be fine after a certain dose of a therapeutic drug, while others might experience severe side-effects. This has piqued scientists for a long time and has given rise to various theories about a possible reason. One such theory is that there are genetic variations in the DMEs that cause people to react differently, and therefore studies into the genes of the DMEs have become a major research focus.

Dr Werely and his colleagues have investigated the genetic makeup of two different DMEs in the South African Black population. We chose the Black population because studies have shown them to be the most genetically diverse group of people on Earth. However, not all Blacks have similar genetic characteristics. We chose to study the genetic variations of the two DMEs in two major ethnic groups from South Africa (Xhosa and Coloured). This was then compared to other major groups in the world," he explains.

The two DMEs in question are glutathione S-transferase (GST) and arylamine N-acetyltransferase 2 (NAT2). GST is actually a family of enzymes that play an important role in the detoxification of certain cancer-causing agents or carcinogens. However, it can also activate certain carcinogens, so scientists say that GSTs may contribute indirectly to cancer susceptibility and predisposition.

NAT2 occurs in the liver, and is primarily involved with the metabolism of isoniazid (INH), a drug used to treat tuberculosis patients. "Certain genetic variations in the NAT2 might be responsible for TB patients developing drug resistance, adverse side-effects or just simply not getting better," Werely explains.

The test results were very interesting. For instance, the genetic variation in GSTT1 (a subclass of GST) showed a similarity between the Xhosa group and the Chinese. Like the Xhosa group, Chinese people also experience a high incidence of oesophageal cancer.

Another subclass of GST, known as GSTP1, is responsible for detoxification of toxins such as those found in cigarette smoke. One specific genetic variation in GSTP1 causes reduced activity of the enzyme, the occurrence of which was very high among the Xhosa group.

"This could increase the risk of smoking-induced diseases, of which oesophageal cancer is one," says Werely.

When turning to NAT2, the results are equally interesting. The genetic variations in NAT2 show similarity between the Coloured population and the Japanese. These variations cause INH to be less effective, which could explain the high prevalence of TB in SA.

"It could be possible that this variation could cause people to experience severe side-effects and therefore they stop taking their medication. Maybe we should look at adjusting their dosage. We think that it is important to study these data because it could be helpful in determining policy guidelines for cancer prevention and chemotherapy," said Dr Werely.