Methyltransferase Subject

Methylation— A few xenobiotics are subject to methylation by methyltransferases, employing 5-adeno-sylmethionine (Figure 30-17) as the methyl donor. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

McLeod HL, Lin JS, Scott EP et al. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994 55 15-20. 

McLeod HL, Lin J-S, Scott EP, Pui C-H, Evans WE. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994 55 15-20. McLeod HL, Miller DR, Evans WE. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993 1341 1151. 

Jones DC, Smart C, Titus A, Blyden G, Dorvril M, Nwadike N. Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther 1993 53 348-353. 

McLeod HL, Pritchard SC, Githang a J, Indalo A, Ameyaw MM, Powrie RH, Booth L, Collie-Duguid ESR. Ethnic differences in thiopurine methyltransferase pharmacogenetics evidence for allele specificity in Caucasian and Kenyan subjects. Pharmacogenetics 1999 9 773-776. 

Adrenaline and noradrenaline are unstable in aqueous solution where they are subjected to spontaneous oxidation. In vivo this mechanism is only relevant under pathophysiological conditions of an catecholamine excess, since two enzymes, the catechol-O-methyltransferase (COMT) and the monoamineoxidase (MAO), inactivate physiological amounts of the transmitters. There are at least two subtypes of the enzyme MAO, A and B, which can be inhibited selectively for therapeutic purposes, for example by moclobemide and selegiline. 

Li T, Vallada H, Curtis D, et al Catechol-O-methyltransferase Vall58Met polymorphism frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. Pharmacogenetics 7 349-353,1997... 

Kubota T, Chiba K. Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT 2, 3A, " 3B and 3C) in 151 healthy Japanese subjects and the inheritance of TPMT 3C in the family... 

In the greatest majority of cases, the methyl group transferred to a xenobiotic derives from the nucleotide S-adenosyl methionine ( ), but 5-methyltetrahydrofollc acid may be the methyl group donor to primary and secondary amines In the brain (49). A variety of N-methyltransferases are known (50) and thlolmethyltransferase has been the subject of much recent attention (51). Xenobiotic phenols undergoing methylation are generally either catechols or phenols with bulky ortho substituents (42). 

TERMINATION OF THE ACTIONS OF CATECHOLAMINES The actions of NE and Epi are terminated by (1) reuptake into nerve terminals by NET (2) dilution by diffusion out of the junctional cleft and uptake at end organs and extraneuronal sites by ENT, OCTl, and OCT2. Subsequent to uptake, the catecholamines are subject to metabolic transformation by MAO and catechol-0-methyltransferase (COMT). In addition, catecholamines are metabolized by sulfotransferases (see Chapter 3). Termination of action by a powerful degradative enzymatic pathway, such as that provided by AChE in cholinergic transmission, is absent from the adrenergic system. Inhibitors of neuronal reuptake of catecholamines (e.g., cocaine, imipramine) potentiate the effects of the... 

The next enzyme in the biosynthetic pathway to norepinephrine and epinephrine, dopamine p-hydroxylase. has been the subject of extensive research into its chemical mechanism and the subject of many enzyme inhibition studies. The inhibitors known to date, however, are primarily of basic biochemical research interest and have no therapeutic relevance. The same is true of phenylethanolamine-N-methyltransferase. the last enzyme in the biosynthesis of epinephrine in the adrenal medulla. 

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