The Metabolism of Pyrazoloacridine (NSC 366140) by Cytochromes P450 and Flavin Monooxygenase in Human Liver Microsomes

Reid, Joel M.; Walker, Denise L.; Miller, Jennifer K.; Benson, Linda M.; Tomlinson, Andy J.; Naylor, Stephen; Blajeski, April L.; LoRusso, Patricia; Ames, Matthew M.

doi:10.1158/1078-0432.ccr-0557-03

Cited by 34 publications

(28 citation statements)

References 24 publications

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“…Furthermore, the haplotype analysis strongly suggests that variation in promoter sequences can modulate the effects of previously characterized structural variants and should be taken into account when assessing genotype/phenotype association studies, or even when prescribing therapeutics for which FMO3 is important for disposition, e.g., sulindac (Hamman et al, 2000), itopride (Mushiroda et al, 2000), or pyrazoloacridine (Reid et al, 2004). Although there are minimal differences in overall FMO3 diversity among the population groups studied, significant differences in individual haplotype frequencies were observed that would contribute to interpopulational differences in the FMO3-dependent metabolism of therapeutics, environmental chemicals, and dietary constituents.…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Koukouritaki¹,

Poch²,

Henderson³

et al. 2006

J Pharmacol Exp Ther

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Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by nonLatino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650CϾG, -2543TϾA, and -2177GϾC) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the AfricanAmerican study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167GϾA (E158K)], H5B [-2650CϾG, 15,167GϾA (E158K), 21,375CϾT (N285N), 21,443AϾG (E308G)], and H6 [15,167GϾA (E158K), 21,375CϾT (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.The flavin-containing monooxygenases (FMOs; EC 1.14.13.8) are a family of microsomal enzymes that catalyze the NADPH-dependent N-and S-oxidation of a variety of therapeutics, environmental toxicants, carcinogens, and nutrients (Krueger and Williams, 2005). The FMO multigene family consists of a five-gene cluster at 1q24.3 (FMO1-4 and FMO6p), a second cluster of five genes at 1q24.2 (FMO7p-11p), and a single gene, FMO5, at 1q21.1, encoding a total of five active proteins in the human (Hernandez et al., 2004).The most recent common precursor for all placental mammals is predicted to have already had a cluster containing FMO1-6P and a separate FMO5 locus that arose from duplication of an ancestral gene approximately 210 to 275 million years ago (Hernandez et al., 2004). Despite the antiquity of the FMO gene family, a sequence comparison among modern FMO enzymes reveals 76 to 86% sequence identity between orthologous proteins, suggesting these genes have been highly conserved.The individual FMO enzymes exhibit broad but distinct substrate specificities (Krueger and Williams, 2005) as well as species-, sex-, tissue-, and age-dependent differences in expression patterns (for review, see Hines, 2006). In the human, FMO3 is the predominant adult hepatic enzyme with a specific conten...

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Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Koukouritaki¹,

Poch²,

Henderson³

et al. 2006

J Pharmacol Exp Ther

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“…There are only several reports about the participation of FMO metabolism in detoxification of other antitumor agents such as pyrazoloacridine derivatives (Reid et al, 2004) or tamoxifen (Krueger et al, 2006). It may be advantageous to develop a drug that is metabolized by FMO enzymes but not by P450s.…”

Section: Antitumor Agent C-1311 Is Metabolized By Fmos Not P450smentioning

confidence: 99%

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

Potęga

Dabrowska²,

Niemira³

et al. 2011

Drug Metab Dispos

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ABSTRACT:5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8-methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDPglucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, P FMO , which is identified as an N-oxide derivative, was identical to P3 R of liver microsomes. P3 R was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3 R ‫؍‬ P FMO . Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C-1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1.

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“…Using CE-ESI-MS three oxidative PZA metabolites, 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide have been identified [26].…”

Section: Anti-tumour Drugsmentioning

confidence: 99%

Recent applications of capillary electrophoresis‐electrospray ionisation‐mass spectrometry in drug analysis

Smyth

2006

Electrophoresis

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This review considers applications in 2004-2005 of capillary electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) to the detection and determination of small molecular mass drug molecules, taken from the Web of Knowledge database. The molecules of small molecular mass less than 1000 Da are chosen according to selected structural classes in which they give ESI signals primarily as [M + H](+) ions. These structural classes are drugs with amine-containing side chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines, other heterocyclic hypnotics, steroids, bioactive compounds containing phenolic groups, and miscellaneous molecules. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion-trap, triple quadrupole and time-of flight mass spectrometers. The review then gives a critical evaluation of these recent CE-ESI-MS analytical methods for the detection and determination of these small molecular mass drug molecules. Analytical information on, for example, sample concentration techniques, CE separation conditions, recoveries from biological media and limits of detection are provided.

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The Metabolism of Pyrazoloacridine (NSC 366140) by Cytochromes P450 and Flavin Monooxygenase in Human Liver Microsomes

Cited by 34 publications

References 24 publications

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

Recent applications of capillary electrophoresis‐electrospray ionisation‐mass spectrometry in drug analysis

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