P450 acetyltransferase

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic Polymorphisms of Human V-Acetyltransferase, Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity , Crit. Rev. Toxicol. 1999, 29, 59 - 124. 

Abbreviations include CYP, cytochrome P450 NAT2, N-acetyltransferase-2 TPMT, thiopurine methyltransferase UGT, glucuronosyl-... 

Wenk M, Todesco L, Krahenbuhl S. Effect of St John s wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females. Br J Clin Pharmacol 2004 57(4) 495 99. Wang LS, Zhou G, Zhu B, et al. St John s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Therapeut 2004 75(3) 191-197. 

Grant DM, Blum M, Meyer UA. Polymorphisms of N-acetyltransferase genes. Xenobiotica 1992 22 1073. Human cytochrome P450s assessment, regulation and genetic polymorphisms. Xenobiotica, 28, number 12, 1998. A series of relevant articles. 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

Wormhoudt LW, Commandeur JN, Vermeulen NP (1999) Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 29 59-124... 

Peroxisome proliferators are also involved in two other metabolic pathways of importance to lipid metabolism. Peroxisomes contain the most of di-hydroxyacetone phosphate acetyltransferase and alkyldihydroxyacetone phosphate synthetase activities. Therefore, they are responsible for initiating most ether glycerolipid biosynthesis. These enzymes are also moderately induced by peroxisome proliferators. Induction of cytochrome P450s by peroxisome proliferators will be addressed separately. 

CYP = cytochrome P450 isoenzyme NAT = N-acetyltransferase P-CP = P-glycoprotein PM, glue = phase II glucuronidation. PMs = poor metabolizers EMs = extensive metabolizers SAs = slow acetylators FAs = fast acetylators. 

ALT alanine aminotransferase AST aspartate aminotransferase CYP cytochrome P450 liver enzyme system NAPQI V-acetyl-p-benzoquinone imine NAT2 N-acetyltransferase 2 genotype... 

Pharmacogenetics involves the impact of genetic variation on drug response. The link between genetically determined variation in drug metabolism enzymes (e.g., cytochrome p450, N-acetyltransferase) and intersubject differences in pharmacokinetics is well established. Likewise, there is an increasing awareness that differences in transporter expression can impact the efficacy and safety of pharmacotherapy. 

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