|Methylation and Acetylation|
The body's ability to methylate organic compounds was discovered by German physician Wilhellm His (pictured left) in 1887, when he isolated N-methyl pyridinium hydroxide form the urine of dogs dosed with pyridine acetate1. He studied metabolism with Schmiedeberg in Strassburg and went on to become director of the first medical clinic in Berlin. A musician and painter,he also pioneered studies in cardiac conduction and campaigned to promote disclosure of the composition of proprietary drugs. In 1954, MacLagan and Wilkinson first described methylation of oxygen in their studies on potential anti-thyroid compounds2. While methylation of phenols is fairly rare the methylation of catechols is quite common. The most significant role O-methylation plays in our physiology was uncovered in 1957 when Axelrod3 and Armstrong and McMillan4 described the O-methylation of adrenaline and noradrenaline.S-Methylation was described in 1958 by Sarcione and Sokal when they reported 2-methyl thio-uracil as a metabolite of thio-uracil in the rat5. The mechanism of methylation didn't become clear until Cantoni elucidated the role of S-adenosyl methionine as the active co-factor in all of these reactions6.
Acetylation was first described by Jaffe and Cohn when they observed a most unusual urinary product following furfural administration to dogs and rabbits7. The product, furfuracrylic acid presumably arose from condensation of the aldehyde with the methyl carbon of acetic acid. Cohn's interest in finding further examples of this type of conjugation led him to administer m-nitrobenzaldehyde to dogs wherein he found m-nitro hippuric acid as a urinary product. Fortunately for his career, he also tried rabbits and there the urine yielded N-acetyl amino benzoic acid, the first N-acetylated metabolite. Over 50 years later F. Lipmann studied the acetylation of sulfanilamides and unraveled the role of coenzyme A in acetylation reactions. This work led to the Nobel Prize for Lipmann in 19539.
Ref: 1His, W., Arch.exp.Path.Pharmak.22:253 (1887), , 2 MacLagan, N.F. and Wilkinson, J.H.,Biochem.J. 56:211 (1954), 3Axelrod, J.,Science 126:400 (1957), 4Armstrong, M.D. and McMillan, A. Fed.Proc. 16:146(1957), 5Sarcione, E.J. and Sokal, J.E., J.Biol.Chem., 231:605 (1958),6Cantoni, G.L., J.Biol.Chem.204:403 (1953), 7M.Jaffe and R. Cohn, Ber.dtsch.Chem.Ges.20:2311 (1887), 8R. Cohn, Z.Physiol.Chem.17:294 (1893), 9Lipmann, F., J.Biol.Chem.160:173 (1945)
Picture: His-Lancet (1934) p.1200 Home
10/2/2016 » 10/6/2016
The 21st International Symposium on Microsomes and Drug Oxidations
10/27/2016 » 10/28/2016
ISSX Workshop: Translating Preclinical Data to Human Clearance and Pharmacokinetics