Tale Of A Missing Gene 

City scientists discover why 
tuberculosis drugs damage liver, reports Biplab Das 

Amal Mukherjee, a 20-year-old patient of pulmonary tuberculosis, undergoing treatment in the SSKM Hospital, complained of a strange problem. He'd developed symptoms of jaundice, few months after he had started his tuberculosis therapy. After a thorough medical check-up, doctors found out that the antituberculosis drugs (ATDs) have brought him the new aliment. Unlike other patients taking the strong drugs, he failed to flush out toxic chemicals generated by them. 

Mukherjee lacks glutathione-S-transferase (GST), an essential enzyme, to destroy the toxic chemicals generated from the ATDs. More than 50 per cent of drug-induced liver damage arises from the problem, find Dr. Bidyut Roy, from the anthropology and human genetics unit of Indian Statistical Institute and Dr. Abhijit Chowdhury from the department of gastroenterology and chest medicine of Institute of Post Graduate Medical Education and Research. 

The team has reported their findings in Journal Of Gastroenterology and Hepatology. The results are based on the tuberculosis patients taking ATDs. 

The ATDs generally include isoniazide, rifamicin and pyrazinaxmide. The drugs are absorbed through the intestine and migrate to liver. There those are converted to toxic chemicals to kill the disease-causing microbes. The next task the liver has to perform is to destroy the toxic substance. "Otherwise, that substance can damage your own tissues," explains Chowdhury. Exactly that happens in patients like Mukherjee. 

GST is the key enzyme of that detoxification step. In liver, there are two types of GSTs - GSTM1 and GSTT1. It was already known that GSTT1 has a little contribution in destroying the toxic derivatives of ATDs. That is why the Calcutta researchers have focused on the GSTM1. 

Looking for the gene that codes for GSTM1 they find the gene is completely absent in people like Amal who suffer from ATD-induced liver damage. As a result, the liver is unable to produce GST and becomes loaded with toxic chemicals. 

The team has studied 33 pulmonary tuberculosis patients who developed liver damage while taking the ATDs. Of them, 17 were found to be deficient of the GSTM1 gene. All of them had high levels of blood bilirubin, a common marker of liver damage. All the patients showed these symptoms within only one month of ATD treatment. In contrast, another group of tuberculosis patients, who have the active GSTM1 gene, were completely free from those symptoms even after one year of ATD treatment. 

"In our body cells, we have two copies of each chromosome. Consequently, we have two sets of all the genes," says Chowdhury. A person devoid of the GSTM1 gene means, he or she lacks both the copies. This type of mutation is called the homozygous null mutation. "It is alarming, at the same time interesting, that quite a large number of people have this type of mutation for an essential gene," Chowdhury says. 

GST is important not only to break down the products of ATDs, but also to detoxify several other compounds. Absence of GSTM1 poses risk for several other complications. Absence if this gene puts a person at greater risk for other diseases like alcoholic liver injury, primary biliary cirrhosis and liver cancer. 

With isoniazide, GST acts on its active form - the acetyle derivative. This can be flushed out from the body by the kidneys without damaging the liver. Had GST not been there, the derivative would have been converted to hydrazine and isonicotinic acid. They give death signals to the cells. 

Researchers did the DNA study with lymphocyte, a particular type of the white blood cell, since it is not possible to get a liver cell from a patient. It proves that GSTM1 is absent not only in liver cells, but also in all body cells. It assures that the loss of GSTM1 gene, or the "null mutation" is inherited through a family line. 

But, what happens to other patients, the rest 16 of 33, who have developed ATD-induced liver damage, in spite of having the GSTM1 gene? "Here comes the environmental and nutrition factors," says Chowdhury. Like any other enzymes, GST is a protein. If a person suffers from malnutrition, there may not be sufficient amino acids to have high yields of the enzyme. The enzyme will then become ineffective. Moreover, a cell has to carry out a number of steps to synthesise a protein from the genetic information. If any of the steps is inhibited, GST will not be available. 

In fact, the problem of ATD-induced damage is multi-dimensional. The researchers have found eight patients developed no liver toxicity symptoms, though the GSTM1 gene is absent in them. This indicates role of some other genes in liver damage. "It may be that some other genes more active to give some other proteins in excess which prevents the damage," says Chowdhury. More research is needed to find out the role of other genes, says Chowdhury. 

Whatever be roles the other genes play, GSTM1 gene definitely one of the most important ones, regarding the damage shows the present study. Liver damage due to ATDs is not very common. According to Chowdhury, 10 per cent of the tuberculosis patients show minor liver problem. Only one per cent of this 10 per cent shows liver damage. But, once the damage occurs, it becomes life threatening. He suggests a genetic screening should be done before administering ATDs.