Figure

Examples of phase II conjugation reactions in drug metabolism.

property found to have important pharmacological consequences (discussed later). To date, little information exists on the regulation of the NAT enzymes, such as whether they can be induced by chemicals. However, reports have suggested that disease states such as acquired immunodeficiency syndrome (AIDS) may down-regulate NAT-2, particularly during active disease.

Sulfotransferases and Methyltransferases

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The co-substrate for these reactions is 3'-phosphoadenosine 5'-phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minox-idil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs 1A1 to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULT1B1 possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULT1E1 has substantial activity toward steroid hormones, especially estra-diol and dehydroepiandrosterone, and toward the anti-

hypertensive minoxidil. SULT2A1 also is active against steroid hormones. Little is known about the substrate specificity of SULT1C1. Regulation of the SULT enzymes appears to be controlled by levels of the available sulfate pool in the body or that of PAPS. Patients who consume a low-sulfate diet or have ingested multiple SULT substrates may be susceptible to inadequate metabolism by this enzyme and thus drug toxicity.

The methyltransferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromol-ecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-l-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. ^-methylation is a well established pathway for the metabolism of neu-rotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and hista-mine. Possibly the most clinically relevant example of MT activity involves S-methylation by the enzyme thiopurine methyltransferase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at high risk for development of severe bone marrow suppression when given normal doses of the chemothera-peutic agent 6-mercaptopurine. Patients are now studied for TPMT activity prior to administration of 6-mercap-topurine so that the dose may be adjusted downward if they are found to be deficient in this enzyme.

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