Intro to Pharm and Tox Topics   

Phase 2 Reactions

Phase 2 reactions are conjugation reactions that almost always deactivate the drug/metabolite, with the important exception of morphine glucuronides. Quantification of the conjugate is usually direct, although may nead to trreat the sampe with enzymes that degrade conjugates (for example beta-glucoronidase, sulfatase) prior to assay.

Uridine diphosphate glucuronic acid (UDPGA) is conjugated to xenobiotics by UDP glucuronosyl transferase. UDPGA is formed in the cytosol from glucose-1-phosphate in a two step reaction catalyzed by <insert> and UDPG dehydrogenase.

The hydroxyl group in phenols and aliphatic alcohols is conjugated with glucuronic acid to form a hemiacetal glucuronide, also known as ether glucuronides:

Carboxilic acids are conjugated through the carboxyl group to form ester gucuronides:

There are many members of the glycosyltransferase superfamily classified into two families:

• UGT1A1 (metabolizes bilirubin), 2, 3, 4, 5, 6, 9 and10
• UGT2B2, 4, 7 (metabolizes morphine and codeine), 15 and 17

Codeine major metabolic pathways yield various active glucoronide metabolites.

Sulfotransferases (SULT) are mostly cytosolic enzymes that transfer a sulfate group to substrates from 3'-phosphoadenosine-5'-phosphosdulfate (PAPS) synthesis in higher organisms. PAPS is formed from ATP and inorganic sulfate in a two step process catalyzed by sulfurylase and APS-kinase:

Substrates for sulphate conjugation include aliphatic alcohols, phenols and aromatic amines.

Some important sulfotransferase substrates are acetaminophen, minoxidil (activated), estradiol and DHEA. There are several sufotransferase families:

• SULTA1 (metabolize acetaminophen, estradiol), 2, and 3 (metabolize acetaminophen).
• SULTB1
• SULTC1
• SULT1E1 (metabolize DHEA, minoxidil)
• SULT2A1

Methyltransferases catalyze the conjugation of a methyl group to a substrate fromS-Adenosyl-L-methionine (AdoMet). AdoMet is synthesized from ATP and methionine by catalysis of methionine adenosyltransferase:

                                        MAT
ATP   +   methionine     AdoMet   +   PPi   +Pi

The methyltrasferases act on substrates like catecholamines, 6-mercaptopurine, and histamines,

Methyltransferases are categorized according to their substrate class:

• catecho-O-methyltransferases (COMT)
• thiopurine methyltransferases (TPMT)
• histamine-N-methyltransferases (HNMT)

N-acetyltransferases (NAT) catalyze the conjugation of an acetyl group from acetyl CoA to a primary amiine substrate:

Some important NAT substrates are dapsone, caffeine, hydralazine and procainamide. There are genetic difference that make individuals "poor acetylators" or "extensive acetylators". Subfamilies of these enzymes are NAT1 and NAT2.

Continue to "Pharmacogenetics" or take a quiz: [Q1].

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