Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic polymorphisms of biotransformation phase I enzymes, cytochrome P450 (CYP1A1 and CYP2D6), and phase II enzymes, glutathione S-transferase (GSTM1 and GSTT1), were analyzed in 204 healthy persons and 348 leukemia patients, who suffered from also acute lymphoblastic leukemia (ALL), acute nonlymphoblastic leukemia (ANLL) chronic myelogenous leukemia (CML), from the Han ethnic group in Changsha City of Hunan Province of China. Our results showed that the frequencies of polymorphisms of CYP1A1, CYP2D6 and GSTT1 among the groups including acute lymphoblastic leukemia, ANLL, chronic myelogenous leukemia and healthy control have no significant differences. The variation of GSTM1-null genotype alone correlated with the development of ANLL. The combined genotypes of GSTM1-null with GSTT1-null, or GSTM1-null with CYP1A1 heterozygous mutant, or GSTM1-null with CYP1A1 heterozygous mutant and CYP2D6 heterozygous mutant, or GSTM1-null with CYP1A1 heterozygous mutant, CYP2D6 heterozygous mutant and GSTT1-null were found in individuals with high risk of ANLL. All these findings suggest that GSTM1-null genotype alone or in coordination with the relevant genotypes of other metabolic enzymes might be susceptibility factors in the etiology of ANLL.
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PMID:Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility. 1841 97

In the present study, we investigated the associations of polymorphisms in cytochrome P450 gene (CYP1A1), glutathione S-transferase genes (GSTM1 and GSTT1) with chronic myelogenous leukemia (CML). A total of 126 patients with CML and 172 healthy volunteers were genotyped, and the DNA was isolated from their blood samples. The polymorphisms were assessed by polymerase chain reaction (PCR) restriction fragment length polymorphism-based methods and multiplex PCR. Logistic regression analyses showed significant risk of CML associated with CYP1A1 Val allele [odds ratio (OR) 3.3, 95% confidence intervals (CI) 1.96-5.53], (p < 0.0001) while CYP1A1 Val/Val homozygotes were observed only in the CML patients. There was statistically significant difference in the frequency of GSTM1 and GSTT1 null genotypes. The GSTT1-null genotype was slightly higher in 27% of CML cases and 16.7% of controls (OR 1.98, 95% CI 1.12-3.5) (p < 0.020). The GSTM1 null was higher in 42.8% of CML cases and 22.7% of controls (OR 2.55, 95% CI 1.54-4.22) (p < 0.00024). The individuals carrying CYP1A1 Ile/Val (AG) and GSTM1 null genotype have 9.9 times higher risk to be CML than those carrying CYP1A1 Ile/Ile (AA) and GSTM1 present genotype (OR 9.9, 95% CI 2.7-36.3) (p < 0.0001). This suggests that the association of the GSTM1 null genotype, either alone or in combination with GSTT1 null, with CYP1AI heterozygous leads to the CML risk.
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PMID:Influence of CYP1A1, GST polymorphisms and susceptibility risk of chronic myeloid leukemia in Syrian population. 2467 54

The associations between CYP1A1 polymorphisms and risk of leukemia have been studied extensively, but the results have been inconsistent. Therefore, in this study, we performed a meta-analysis to clarify associations of three CYP1A1 polymorphisms (T3801C, A2455G, and C4887A) with the risks of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Medline, EMBASE, and China National Knowledge Infrastructure databases were searched to collect relevant studies published up to April 20, 2015. The extracted data were analyzed statistically, and pooled odds ratios with 95% confidence intervals were calculated to quantify the associations. Overall, 26 publications were included. Finally, T3801C was associated with an increased risk of AML in Asians under the dominant model. For A2455G, the risk of ALL was increased among Caucasians in the recessive model and the allele-contrast model; A2455G was also associated with an increased risk of CML among Caucasians under the recessive model, dominant model, and allele-contrast model. For C4887A, few of the included studies produced data. In conclusion, the results suggest that Asians carrying the T3801C C allele might have an increased risk of AML and that Caucasians with the A2455G GG genotype might have an increased risk of ALL. Further investigations are needed to confirm these associations.
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PMID:Genetic polymorphisms of CYP1A1 and risk of leukemia: a meta-analysis. 2649 62

Ponatinib, a pan-BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML), causes severe side effects including vascular occlusions, pancreatitis, and liver toxicity, although the underlying mechanisms remain unclear. Modifications of critical proteins through reactive metabolites are thought to be responsible for a number of adverse drug reactions. In vitro metabolite screening of ponatinib with human liver microsomes and glutathione revealed unambiguous signals of ponatinib-glutathione (P-GSH) adducts. Further profiling of human cytochrome P450 (P450) indicated that CYP1A1 was the predominant P450 enzyme driving this reaction. P-GSH conjugate formation paralleled the disappearance of hydroxylated ponatinib metabolites, suggesting the initial reaction was epoxide generation. Mouse glutathione S-transferase p1 (mGstp1) further enhanced P-GSH adduct formation in vitro. Ponatinib pharmacokinetics were determined in vivo in wild-type (WT) mice and mice humanized for CYP1A1/2 and treated with the CYP1A1 inducers 2,3,7,8-tetrachlorodibenzodioxin or 3-methylcholanthrene. Ponatinib exposure was significantly decreased in treated mice compared with controls (7.7- and 2.2-fold for WT and humanized CYP1A1/2, respectively). Interestingly, the P-GSH conjugate was only found in the feces of CYP1A1-induced mice, but not in control animals. Protein adducts were also identified by liquid chromatography-tandem mass spectrometry analysis of mGstp1 tryptic digests. These results indicate that not only could CYP1A1 be involved in ponatinib disposition, which has not been previously reported, but also that electrophilic intermediates resulting from CYP1A1 metabolism in normal tissues may contribute to ponatinib toxicity. These data are consistent with a recent report that CML patients who smoke are at greater risk of disease progression and premature death.
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PMID:Novel Pathways of Ponatinib Disposition Catalyzed By CYP1A1 Involving Generation of Potentially Toxic Metabolites. 2888 92