| 2019 | Association of Drug Metabolic Enzyme Genetic Polymorphisms and Adverse Drug Reactions in Patients Receiving Rifapentine and Isoniazid Therapy for Latent Tuberculosis. | Int J Environ Res Public Health | Weekly rifapentine and isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015-4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022-2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250-2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen. |
| 2016 | Effect of antituberculosis treatment on CYP2C19 enzyme activity in genetically polymorphic South Indian Tamilian population. | Fundam Clin Pharmacol | Patients on antituberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which require drug therapy. Rifampicin is a pleiotropic inducer of CYP enzymes, and isoniazid is an enzyme inhibitor. Genetic variations are common in the gene coding for CYP2C19 enzyme. These variations would be important in predicting the individual variations in CYP2C19 activity. The objectives of the study were to find the net effect of 1-month ATT on CYP2C19 enzyme activity and its association with CYP2C19 genetic polymorphisms. Newly diagnosed tuberculosis patients (n = 125) were included in the study. Before commencing ATT, they were given a single dose of omeprazole 20 mg as a probe drug for CYP2C19. Blood sample was collected after 3 h to carry out phenotyping for CYP2C19 enzyme by measuring omeprazole hydroxylation index (OHI) using LC-MS/MS. The phenotyping procedure was repeated after 1 month of ATT. CYP2C19 genotyping was carried out by PCR-RFLP method. Significant reduction in OHI was observed after 1 month of ATT in all the metabolizer groups. The percentage reduction in OHI was maximum with poor metabolizers, 84.1 (IQR - 74.6, 86.6), and minimum with ultra-rapid metabolizers, 39.6 (IQR - 12.7, 54.7). CYP2C19 enzyme induction is predominant in patients after 1 month of antituberculosis treatment (ATT). Genetic variations in the enzyme could not clearly explain the interindividual differences in induction. There is a potential risk of drug failure/adverse effect in poor metabolizers regardless of their genotype after ATT. |
| 2015 | Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes. | Biol Pharm Bull | The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4. |
| 2014 | Inhibition of cytochrome P450 by ethambutol in human liver microsomes. | Toxicol Lett | Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The K(i) value of ethambutol for CYP1A2 was 1.4 μM and for CYP2E1 was 2.9 μM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and β-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0 μM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10 μM and long half-life of ~22 h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations. |
| 2011 | Simple, direct, and informative method for the assessment of CYP2C19 enzyme inactivation kinetics. | Drug Metab Dispos | Many clinically relevant drug interactions involving cytochrome P450 inhibition are mediated by mechanism-based inactivation (MBI). Time-dependent inhibition is one of the major features distinguishing between reversible inhibition and MBI. It thus provides a useful screening approach for early drug interaction risk assessment. Accordingly, we developed an easy and informative fluorometric method for the assessment of CYP2C19 enzyme inactivation kinetics. Dibenzylfluorescein (DBF) is widely used as a profluorescent probe substrate for P450 activity and inhibition assays, but its use has been considered to be limited to traditional endpoint assays. We monitored CYP2C19-catalyzed metabolism of DBF using synthesized fluorescein benzyl ester and fluorescein benzyl ether along with commercially available fluorescein as intermediate standards. Furthermore, we demonstrated the use of DBF in a kinetic assay as a progress curve analysis for straightforward determination of whether a compound is a time-dependent inactivator of CYP2C19. The recombinant human CYP2C19 inactivation kinetics of isoniazid, ticlopidine, and tranylcypromine were evaluated, and their key kinetic parameters were measured from the same experiment. The known mechanism-based inactivators, isoniazid and ticlopidine, exhibited clear time-dependent inactivation with K(I) and k(inact) values of 250.5 ± 34 μM and 0.137 ± 0.006 min(-1) and 1.96 ± 0.5 μM and 0.135 ± 0.009 min(-1), respectively. Tranylcypromine did not display any time-dependent inhibition, which is consistent with its reported mechanism of competitive inhibition. In summary, DBF is suitable for use in the progress curve analysis approach and can be used as an initial screen to identify compounds that require more detailed investigations in drug interaction optimization. |
| 2011 | NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption. | Eur J Clin Pharmacol | It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE.We enrolled 62 patients with ATD-induced MPE (mean age 47.2 ± 19.0, male 59.7%) and 159 patients without any adverse reactions to ATD (mean age 42.8 ± 17.6, male 65.4%), among patients with pulmonary tuberculosis (TB) and/or TB pleuritis and treated with first-line anti-TB medications, including isoniazid, rifampin, ethambutol, and pyrazinamide. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in four drug-metabolizing enzymes (N-acetyltransferase 2 (NAT2), cytochrome P450 (CYP) 2 C9, CYP2C19, and CYP2E1) among patients with ATD-induced MPE and patients tolerant to ATD using a multivariate logistic regression analysis. These analyses were made without identification of the responsible ATD.-1565 C > T of CYP2C9 showed a significant association with ATD-induced MPE (P = 0.022, OR = 0.23, 95% CI 0.07-0.78), with a lower frequency of genotypes carrying minor alleles (CT or TT) in the case group than in the controls. Additionally, W212X of CYP2C19 was significantly associated with the risk of ATD-induced MPE (P = 0.042, OR = 0.27, 95% CI 0.09-0.82). In an analysis of the CYP2C19-CYP2C9 haplotypes (-1418 C > T_W212X_-1565 C > T_-1188 C > T), ht3[T-A-T-C] showed a significant association with the development of ATD-induced MPE (P = 0.012, OR = 0.13, 95% CI 0.03-0.57). No significant associations between the other genetic polymorphisms and ATD-induced MPE were observed.CYP2C19 and CYP2C9 genetic polymorphisms are significantly associated with the risk of developing ATD-induced MPE, and the genetic variants in NAT2 and CYP2E1 are not closely related to the development of this adverse reaction. |
| 2009 | Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. | Pharmacogenomics | Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis.We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls.Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types.These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction. |
| 2010 | Pharmacogenetics of phase I and phase II drug metabolism. | Curr Pharm Des | Genetic variation in the receptors and other intracellular targets that mediate the pharmacodynamic effects of drugs can affect therapeutic outcomes. However, at present greater knowledge is available concerning the extent of gene variation in drug metabolizing enzymes that determine drug pharmacokinetics and, in turn, drug efficacy and toxicity. Information on the incidence of polymorphisms in the cytochrome P450 (CYP) genes that mediate phase I biotransformation is increasing, although the level of detail in the case of phase II conjugation enzymes, such as the UDP-glucuronosyltransferases (UGTs) and N-acetyltransferases (NATs), is not as extensive. It is now apparent that defective alleles that encode variant CYPs, UGTs, NATs and other biotransformation enzymes can influence the outcome of therapy. Diminished rates of drug clearance can increase the incidence of toxicity from many drugs, but may also enhance efficacy, as in the case of the proton-pump inhibitor omeprazole, that maintains therapeutic serum concentrations in individuals that carry null alleles for CYP2C19. Variant alleles of UGT1A1 are less capable of conjugating and eliminating SN-38, the active form of the topoisomerase inhibitor irinotecan, and defective alleles for NAT2 are responsible for the well-described acetylation polymorphism that leads to impaired clearance of isoniazid and other agents. This review focuses on reports that relate pharmacogenetic variation in phase I and phase II enzymes to the safety and toxicity of drug therapy and highlights a number of themes that have emerged recently that may be developed to streamline therapy for individuals. |
| [Cytochrome P450 and NAT2 polymorphisms and drug metabolism in DOTS]. | Rev Invest Clin | It has been described an increase of the frequency of Directly Observed Therapy Short-course (DOTS) failure in countries with high rates of mycobacterial drug resistance. This increase could be due to the standardized doses of DOTS results in low or insufficient dosage of drugs in plasma. Several members of cytochrome P450 enzymes superfamily could explain the variations on acetylation velocity and in drug disposition. A population with slow acetylation has a higher risk of toxicity, as that potent inhibition of cytochrome P450 (CYP450) isoforms by isoniazid (CYP2C19 y CYP3A) are dependent of INH plasmatic concentration. This inhibitory effect has been described also for CYP12, CYP2C9 and CYP2E1. INH is metabolized by N-acetyltransferase 2 (NAT2). The wide variability interethnic and intraethnic in acetylation velocity is associated with the polymorphisms of NAT2. Patients with rapid acetylation have plasmatic concentration of INH low or insufficient which induces treatment failure. The study of genotypes of P450 and NAT2 allow us to predict therapeutic and individualized dosages. |
| 2006 | An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid. | Br J Clin Pharmacol | To characterize potential mechanism-based inactivation (MBI) of major human drug-metabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid.Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co- and preincubation with MAO inhibitors. Inactivation kinetic constants (KI and kinact) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation.Hydrazine MAO inhibitors generally exhibited greater inhibition of CYP following preincubation, whereas this was less frequent for the propargylamines, and tranylcypromine and moclobemide. Phenelzine and isoniazid inactivated all CYP but were most potent toward CYP3A and CYP2C19. Respective inactivation kinetic constants (KI and kinact) for isoniazid were 48.6 microm and 0.042 min-1 and 79.3 microm and 0.039 min-1. Clorgyline was a selective inactivator of CYP1A2 (6.8 microm and 0.15 min-1). Inactivation of CYP was irreversible, consistent with metabolite-intermediate complexation for isoniazid and clorgyline, and haeme destruction for phenelzine. With the exception of phenelzine-mediated CYP3A inactivation, glutathione and superoxide dismutase failed to protect CYP from inactivation by isoniazid and phenelzine. Glutathione partially slowed (17%) the inactivation of CYP1A2 by clorgyline. Alternate substrates or inhibitors generally protected against CYP inactivation.These data are consistent with mechanism-based inactivation of human drug-metabolizing CYP enzymes and suggest that impaired metabolic clearance may contribute to clinical drug-drug interactions with some MAO inhibitors. |
| 2004 | Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities. | J Pharmacol Sci | The potential for drug-drug interactions mediated by the inhibition of cytochrome P-450 (CYP) were concerned during antituberculosis therapy. However, the information regarding human CYP inhibition by antituberculosis drugs is limited to isoniazid. In the current study, we examined the inhibitory effects of pyrazinamide and ethionamide, both of which are chemically related to isoniazid, on the CYP-mediated activities in human liver microsomes and compared them to that of isoniazid. No remarkable effects on any CYP activities were observed by pyrazinamide and ethionamide. In contrast, in addition to the reported inhibitory effect of isoniazid on CYP1A2, CYP2A6, CYP2C19, and CYP3A activities, our results newly showed its effect on CYP2C9 and CYP2E1 activities. Isoniazid showed potent direct inhibitory effect on S-warfarin 7-hydroxylation, while a preincubation step in the presence of NADPH was needed to inhibit chlorzoxazone 6-hydroxylation. Furthermore, irreversible inhibition of CYP2C19 activity by isoniazid was also observed in the dilution study. These results suggested that pyrazinamide and ethionamide did not seem to cause drug interactions mediated by the inhibition of CYP. In contrast, isoniazid might contribute to the severe drug interactions by a different inhibitory mechanism depending on each of the CYP isozymes, in addition to the reported observations. |
| 2003 | Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. | Drug Metab Dispos | Cultured human hepatocytes are a valuable in vitro system for evaluating new molecular entities as inducers of cytochrome P450 (P450) enzymes. The present study summarizes data obtained from 62 preparations of cultured human hepatocytes that were treated with vehicles (saline or dimethylsulfoxide, 0.1%), beta-naphthoflavone (33 microM), phenobarbital (100 or 250 microM), isoniazid (100 microM) and/or rifampin (20 or 50 microM), and examined for the expression of P450 enzymes based on microsomal activity toward marker substrates, or in the case of CYP2C8, the level of immunoreactive protein. The results show that CYP1A2 activity was markedly induced by beta-naphthoflavone (on average 13-fold, n = 28 preparations), and weakly induced by phenobarbital (1.9-fold, n = 25) and rifampin (2.3-fold, n = 22); CYP2A6 activity tended to be increased with phenobarbital (n = 7) and rifampin (n = 3) treatments, but the effects were not statistically significant; CYP2B6 was induced by phenobarbital (6.5-fold, n = 13) and rifampin (13-fold, n = 14); CYP2C8 was induced by phenobarbital (4.0-fold, n = 4) and rifampin (5.2-fold, n = 4); CYP2C9 was induced by phenobarbital (1.8-fold, n = 14) and rifampin (3.5-fold, n = 10); CYP2C19 was markedly induced by rifampin (37-fold, n = 10), but relatively modestly by phenobarbital (7-fold, n = 9); CYP2D6 was not significantly induced by phenobarbital (n = 5) or rifampin (n = 5); CYP2E1 was induced by phenobarbital (1.7-fold, n = 5), rifampin (2.2-fold, n = 5), and isoniazid (2.3-fold, n = 5); and, CYP3A4 was induced by phenobarbital (3.3-fold, n = 42) and rifampin (10-fold, n = 61), but not by beta-naphthoflavone. Based on these observations, we generalize that beta-naphthoflavone induces CYP1A2 and isoniazid induces CYP2E1, whereas rifampin and, to a lesser extent phenobarbital, tend to significantly and consistently induce enzymes of the CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A subfamilies but not the 2D subfamily. |
| 2001 | Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A. | Antimicrob Agents Chemother | Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its K(m) value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 microM INH (approximately 6.86 microg/ml), the activities of these isoforms decreased by approximately 40%. INH did not show significant inhibition (<10% at 50 microM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (K(i) values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The mean K(i) values (+/- standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 +/- 6.2 and 13 +/- 2.4 microM, respectively. INH showed potent noncompetitive inhibition of CYP3A (K(i) = 51.8 +/- 2.5 to 75.9 +/- 7.8 microM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (K(i) = 110 +/- 33 microM) and a competitive inhibitor of CYP2D6 (K(i) = 126 +/- 23 microM), but the mean K(i) values for the inhibition of CYP2C9 and CYP1A2 were above 500 microM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact. |
| 1999 | Populations and genetic polymorphisms. | Mol Diagn | Population frequencies of many polymorphic genes of pharmacogenetic interest depend on race or ethnic specificity. Association of these genes with person-to-person differences in drug effectiveness (hypersensitivity or resistance) and drug toxicity may also depend on the racial or ethnic characteristics of a population. Information about ethnic specificity is an integral part of pharmacogenetics because it can suggest a starting point for further study of these traits, tailoring drug therapy to the individual patient, and rational development and clinical trials of new drugs. Ethnic specificities of several medically important metabolic traits serve to illustrate these ideas. Among the traits considered is primaquine sensitivity, a sex-linked trait attributed to glucose-6-phosphate dehydrogenase deficiency that mainly affects males among African, Mediterranean, and Oriental people. Additional examples include the remarkable sensitivity of the Japanese to alcohol (ethanol) compared with whites; the ethnic specificity of the cytochrome P-450 enzyme CYP2D6* (debrisoquine/sparteine) polymorphism that results in poor, extensive, and ultrarapid metabolizers of at least 30 drugs; the CYP2C19* (mephenytoin) polymorphism that accounts for variable metabolism of proguanil, omeprazole, and certain barbiturates; and the polymorphic (NAT2*) acetylation of hydrazine and aromatic amine drugs, such as isoniazid, hydralazine, and sulfasalazine. |
| 1998 | [Interindividual differences in efficacy and toxicity induced by therapeutic drugs and xenobiotics in relation to genetic polymorphisms in xenobiotic metabolizing enzymes]. | Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku | Humans incessantly ingest wide-variety of chemicals through the administration of therapeutic drugs, diets and beverages. Humans are also exposed to environmental mutagens and carcinogens and substances causing endocrine disruption. Metabolism and disposition have been regarded as one of the most important determinants of efficacy and toxicity induced by ingested chemicals, since remarkable individual difference was observed in the plasma concentration and/or urinary excretion after the administration of wide variety of therapeutic drugs such as isoniazid, sulfamethazine, debrisoquin, sparteine, mephenytoin and so on. This variability is resulted from pharmacogenetically regulated difference in the activities of xenobiotic metabolizing enzymes (so called genetic polymorphisms). Polymorphic appearance of xenobiotic metabolism has also been observed with various toxic substances such as ethanol, acetaldehyde, benzene, organic phosphates and environmental mutagens and carcinogens. Enzymes which show genetic polymorphisms include cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, CYP2C19, CYP2D6 and CYP2E1) and phase II drug metabolizing enzymes (arylamine N-acetyltransferases, glutathione S-transferases and UDP-glucuronosyl transferases). A number of mutations on the genes encoding polymorphic xenobiotic metabolizing enzymes have been associated with the remarkable individual difference in the metabolism and disposition in vivo. Individuals with distinct alleles of genes which encode defective enzymes have been shown to be at higher risk to toxic side effects by therapeutic drugs and more susceptible to certain malignant diseases. Research has to be conducted for each human race concerning risk assessment of chemicals, since ethnic differences in frequency of distinct alleles of genes encoding xenobiotic metabolizing enzymes are reported. In case of type 1 Crigler-Najjar syndrome causing unconjugated hyperbilirubinemia, complete loss of bilirubin-detoxifing UDP-glucuronosyl transferase has been attributed to nonsense, missense, and/or frameshift mutations that occurred at various sites on UGT1 gene. Thus, genetic polymorphisms of xenobiotic metabolizing enzymes are one of the most important factors influencing efficacy of therapeutic drugs and toxicity by wide-variety of chemicals. |