Catechol-O-methyl transferase

About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.

Glucuronidation of entacapone, nitecapone, tolcapone, and some other nitrocatechols by rat liver microsomes.

Abstract: Purpose. Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds.

Inhibitors of catechol-O-methyltransferase sensitize mice to pain.

Abstract: BACKGROUND AND PURPOSE Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom COMT polymorphisms modulate pain and opioid analgesia in humans In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice EXPERIMENTAL APPROACH We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor We also tested CGP 28014, an indirect inhibitor of COMT enzyme Effects of OR-486 on thermal nociception were also studied in COMT deficient mice Effects on spinal pathways were assessed in rats given intrathecal nitecapone KEY RESULTS After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration These effects were still present after chronic treatment with COMT inhibitors for 5 days Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation CGP 28014 shortened paw flick latencies OR-486 did not modify hot plate times in Comt gene deficient mice Intrathecal nitecapone modified neither thermal nor mechanical nociception CONCLUSIONS AND IMPLICATIONS Pro-nociceptive effects of COMT inhibitors were confirmed The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord COMT protein was required for these actions

Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder

Abstract: Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val158Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.