**4. Conclusion**

containing these genes revealed two regions flanking *GSTT1*, HA3 and HA5, with more than 90% homology. HA3 and HA5 contain two identical 403-bp repeats and the occurence of *GSTT1\*0* allele is probably caused by homologous recombination between the two regions [78]. In humans, *GSTT1* is also expressed in erythrocytes and probably plays a global role in early

**Figure 5.** Structural localization of gene cluster encoding the GST subfamily theta (chromosome 22q11.2). The *GSTT1* null allele (*GSTT1\*0*) arises by homologous recombination of the left and right 403-bp repeats, which results in a 54-

Deficiencies in the GST activity due to the null genotypes of *GSTM1* and *GSTT1* may modulate susceptibility to the development of hepatotoxicity induced by drugs and xenobiotics. Furthermore, it was observed that the frequencies of *GSTT1\*0* and *GSTM1\*0* alleles vary within different ethnic groups [78, 82]. Liver injury induced by INH has been associated with the depletion of glutathione content and reduction of GST activity in an animal model for

In 2001, Roy and colleagues demonstrated that individuals, homozygous for the null *GSTM1,* had a relative risk of 2.12 for developing hepatotoxicity induced by anti-TB drugs. However, these authors found no association of the *GSTT1* null genotype with this side effects [54]. Similarly, another study in the Thai population found that only the *GSTM1* null genotype increases the risk of liver injury (OR 2.23, 95% CI 1.07 to 4.67) [93]. The opposite was observed by Leiro and colleagues: individuals with the *GSTT1* null genotype had an increased risk of developing hepatotoxicity induced by anti-TB drugs and no significant association was observed between GSTM1\*0/\*0 genotype and liver injury [94]. These studies suggest a

protective effect of glutathione S-transferases to the hepatotoxic effects of isoniazid.

null genotypes and hepatotoxicity induced by anti-TB drugs [97].

On the other hand, recent studies in different population showed no relationship between GSTM1\*0/\*0 or GSTT1\*0/\*0 genotypes and liver injury during anti-TB treatment [58, 95, 96]. In a population-based prospective antituberculosis treatment coort in China, a more robust case-control study was conducted and there was no statistically significant association between

detoxification of xenobiotics and carcinogens.

116 Tuberculosis - Current Issues in Diagnosis and Management

kb deletion containing the entire *GSTT1* gene. Figure adapted from [78].

hepatotoxicity by anti-TB drugs [22].

The concept of personalized medicine is not really new, but it has been receiving increasing attention in recent years for improval of drug regulation and medical guidelines. There is considerable interindividual variability in metabolism, partly due to human differences on a genetic level. Genetic polymorphisms in drug-metabolizing enzymes can affect enzyme activity and may cause differences in treatment response or drug toxicity, for example, due to an increased formation of reactive metabolites. Such polymorphisms may explain differences in incidence of anti-TB drugs induced hepatotoxicity between different populations.

Genotyping cannot completely predict the phenotype on an individual level because of to the additional contribution of epigenetic, endogenous and environmental factors. However, pharmacogenetics is able to add important information in many cases where therapeutic drug scheme is inappropriate or not sufficient. Nowadays, we can cite three examples of personal‐ ized medicine application in clinical practice, (i) AIDS treatment (abavir / skin hypersensitiv‐ ity / *HLA-B\*5701*), (ii) anticoagulation (warfarin / bleeding / *CYP2C9*) and (iii) treatment of acute lymphoblastic leukemia (azathioprine / treatment resistence / *TPMT*) [98].

Although limited information exists regarding isoniazid concentrations that cause toxic reactions, it has been proposed to adjust isoniazid dosage depending on individuals acetylator status: a lower dosage for slow acetylators to reduce the risk of liver injury and a higher isoniazid dosage for fast acetylators to increase the early bactericidal activity and thereby lower the probability of treatment failure [50]. However, more robust clinical prospective studies are needed to evaluate the real contribution of these different polyporphirms in the occurence of liver side effects during anti-TB treatment. Future studies should include larger sample size, different ethnic population, simultaneous analysis of different genetic markers, different degrees of liver injury and consideration of possible confounding factors.
