Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disulfiram is used in the treatment of alcoholism to inhibit the enzyme aldehyde dehydrogenase. Disulfiram is rapidly reduced in vivo to form diethyldithiocarbamate (DDC), and DDC can undergo methyl conjugation to form S-methyl-DDC. Human tissues contain two separate genetically regulated enzymes that can catalyze thiol S-methylation. Thiol methyltransferase (TMT) is a microsomal enzyme that preferentially catalyzes, the S-methylation of alipathic sulfhydryl compounds, whereas thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds. Our experiments were performed to determine whether human liver microsomal and/or cytosolic preparations could catalyze the S-methylation of DDC, and, if so, to determine whether TMT or TPMT might be the enzymes involved. We found that both human liver microsomes and cytosol could catalyze DDC S-methylation. The microsomal activity displayed biphasic substrate kinetics, with apparent Km values for DDC of 7.9 and 1500 microM for the high- and low-affinity activities, respectively. The high-affinity activity had an apparent Km value for S-adenosyl-L-methionine, the methyl donor for the reaction, of 5.8 microM. The thermal inactivation profile and response to methyltransferase inhibitors of the high-affinity microsomal DDC S-methyltransferase activity were similar to those of human liver microsomal TMT. In addition, TMT activity and the activity catalyzing the S-methylation of DDC were highly correlated in 19 individual liver samples (rs = 0.956; P < .0001). Hepatic cytosolic DDC S-methyltransferase activity had an apparent Km value for DDC of 95 microM. The cytosolic enzyme which catalyzed DDC S-methylation and TPMT activity had similar thermal inactivation profiles, similar patterns of response to methyltransferase inhibitors and the two activities coeluted during ion exchange chromatography. Furthermore, the activities of TPMT and cytosolic DDC S-methyltransferase were highly correlated in 20 individual liver samples (rs = 0.963; P < .0001). These results were compatible with the conclusion that both TMT and TPMT could catalyze the S-methylation of DDC in the human liver. Because the activities of both TMT and TPMT are controlled by inheritance, our observations raise the possibility of pharmacogenetic variation in the biotransformation and therapeutic effect of DDC in humans.
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PMID:Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. 839 51

The goal of chemotherapy is the elimination of tumor cells from the host. This is achieved by the use of therapeutic agents that are often more harmful to normal tissues than to the targeted tumor. Many chemotherapeutic agents are designed to damage cell replication machinery either directly at the level of DNA or indirectly, by inhibiting enzymes involved with DNA repair and synthesis. Novel therapeutic agents that exert their effects at signal transduction pathways have advanced chemotherapy; however, a role for the classic chemotherapeutic agents remains. These classic agents are associated with tumor cell resistance, toxicity, and occasionally secondary neoplasia. Current practices for the dosing of therapeutic agents rely on height and body surface measurements or drug monitoring and Bayesian adaptive control. Pharmacogenetics is emerging as an alternate approach to managing chemotherapy that may prevent undertreatment while avoiding overtreatment and associated toxicities. By determining the polymorphic genetic makeup of the host and, in some instances, the altered genetic expression of the tumor, chemotherapy can be tailored for interindividual response and toxicity avoidance. Chemotherapy is particularly applicable to the pharmacogenetic approach to tailored therapy for a number of reasons. The margin of safety is low with chemotherapeutic agents. Some drugs require biotransformation for activation. Drug activation correlates with toxicity. The pathways of drug clearance or inactivation exhibit polymorphic differences. Interindividual, race-specific, and age-related responses to chemotherapeutic agents are common. Last, drug resistance can be inherent to the tumor as a result of the suppression of apoptosis. Variations in response and toxicity to a specific drug can be caused by alterations in drug-metabolizing enzymes or receptor expression. These effects can be classed as pharmacokinetic and pharmacogenetic differences. Some of the genes known to display polymorphic differences include FLT3 receptor tyrosine kinase, FCG3RA IgG FC receptor, thymidylate synthase, methylenetetrahydrofolate reductase, thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, aldehyde dehydrogenase, glutathione S-transferase, uridine diphosphate glyuronosyl transferases, N-acetyl transferases, cytochrome P450, and the DNA repair enzymes XPD and XRCC1. To be successful a pharmacogenetic approach to individualized chemotherapy must selectively take advantage of a determination of direct enzyme activity, gene expression, and genotype.
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PMID:Pharmacogenetics in cancer chemotherapy: balancing toxicity and response. 1522 71