Variation of Hepatic Methotrexate 7-Hydroxylase Activity in Animals and Humans

Kawa, Shigeyuki; Sugihara, Kazumi; Nakatani, Keiko; Ohta, Shigeru; Oh-hara, Toshinari; Ninomiya, Shinichi; Green, Carol E.; Tyson, Charles A.

doi:10.1080/152165499306487

Cited by 23 publications

(26 citation statements)

References 21 publications

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“…Interindividual variability in hAOX1 in vitro activity has been reported in humans (Kitamura et al, 1999b;Al-Salmy, 2001), although the underlying determinants of these variations have never been investigated (Beedham et al, 2003). Gender may be one such determinant.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

et al. 2012

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ABSTRACT:Aldehyde oxidase (AO) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. AO is active as a homodimer, and each 150-kDa monomer binds two distinct [2Fe2S] clusters, FAD, and the molybdenum cofactor. AO has an important role in the metabolism of drugs based on its broad substrate specificity oxidizing aromatic aza-heterocycles, for example, was obtained with a purity of 95% and a yield of 50 g/l E. coli culture. Site-directed mutagenesis of the hAOX1 cDNA allowed the purification of protein variants bearing the amino acid changes R802C, R921H, N1135S, and H1297R, which correspond to some of the identified SNPs. The hAOX1 variants were purified and compared with the wild-type protein relative to activity, oligomerization state, and metal content. Our data show that the mutation of each amino acid residue has a variable impact on the ability of hAOX1 to metabolize selected substrates. Thus, the human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. Our results indicate that the presence of these allelic variants should be considered for the design of future drugs.

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Section: Introductionmentioning

confidence: 99%

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

et al. 2012

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“…Cancer Prevention Research oxidase is responsible for the metabolism of many antiviral and anticancer agents (34,35). Interestingly, aldehyde oxidase activity is influenced by the levels of testosterone and growth hormones, leading to gender, species, and strain differences in the enzyme activity (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice

Yoo

Chuang

Byun

et al. 2008

Cancer Prevention Research

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Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc Min/+ (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissuespecific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.

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“…For example, when monkey and rabbit are compared, the following considerably complicated situation seems to arise. Approximately 2 orders of magnitude higher methotrexate 7-hydroxylase activity was shown in rabbit compared with that of monkey (Kitamura et al, 1999). Likewise, rabbit exhibited 2 to 3 orders of magnitude higher activity toward cinchonidine 2Ј-oxidation than did that of monkey (Itoh et al, 2006).…”

Section: And (؉)-4-(4-cyanoanilino)-56-dihydro-7-hydroxy-7h-cyclopenmentioning

confidence: 84%

“…The enzyme catalyzes the nucleophilic, but not electrophilic, oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. In addition, the enzyme can also catalyze the reductive-ring cleavage metabolism of the atypical antipsychotic drug ziprasidone in humans (Prakash et al, 1997;Beedham et al, 2003).Being fundamentally different from XOR, AOX1-catalyzed drug metabolism results in marked species differences, which have been well documented for methotrexate (Jordan et al, 1999;Kitamura et al, 1999), famciclovir (Rashidi et al, 1997), cinchona alkaloids (Beedham et al, 1992;Itoh et al, 2006), zonisamide (Kitamura et al, 2001), and a monoamine oxidase A inhibitor RS-8359 (Takasaki et al, 1999(Takasaki et al, , 2005Itoh et al, 2005Itoh et al, , 2006. As a rule, AOX1 activity is high in monkeys and humans, moderate to low in rabbits, rats, and mice, and deficient in dogs.…”

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confidence: 99%

A Single Amino Acid Substitution Confers High Cinchonidine Oxidation Activity Comparable with That of Rabbit to Monkey Aldehyde Oxidase 1

Fukiya

Itoh²,

Yamaguchi³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Aldehyde oxidase 1 (AOX1) is a major member of the xanthine oxidase family belonging to the class of complex molybdo-flavoenzymes and plays an important role in the nucleophilic oxidation of N-heterocyclic aromatic compounds and various aldehydes. The enzyme has been well known to show remarkable species differences. Comparing the rabbit and monkey enzymes, the former showed extremely high activity toward cinchonidine and methotrexate, but the latter exhibited only marginal activities. In contrast, monkey had several times greater activity than did rabbit toward zonisamide and (؉)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine [(S)-RS-8359]. In this report, we tried to confer high cinchonidine oxidation activity comparable with that of rabbit AOX1 to monkey AOX1. The chimera proteins prepared by restriction enzyme digestion and recombination methods between monkey and rabbit AOX1s indicated that the sequences from Asn993 to Ala1088 of rabbit AOX1 are essential for the activity. The kinetic parameters were then measured using monkey AOX1 mutants prepared by site-directed mutagenesis. The monkey V1085A mutant acquired the high cinchonidine oxidation activity. Inversely, the reciprocal rabbit A1081V mutant lost the activity entirely: amino acid 1081 of rabbit AOX1 corresponding to amino acid 1085 of monkey AOX1. Thus, cinchonidine oxidation activity was drastically changed by mutation of a single residue in AOX1. However, this might be true for bulky substrates such as cinchonidine but not for small substrates. The mechanism of substrate-dependent species differences in AOX1 activity toward bulky substrates is discussed.Aldehyde oxidase (AO, EC 1.2.3.1) is a major member of the xanthine oxidase family belonging to the molybdo-flavoenzymes (MFEs) together with xanthine oxidoreductase (XOR; xanthine dehydrogenase form, EC 1.1.1.204; xanthine oxidase form, EC 1.1.3.22) (Beedham, 1985(Beedham, , 1987(Beedham, , 1998(Beedham, , 2002Kitamura et al., 2006;Garattini et al., 2008;Schumann et al., 2009). Aldehyde oxidase 1 (AOX1) consists of a homodimer with a subunit molecular mass of approximately 150 kDa. Each subunit is made up of a 20-kDa N-terminal domain containing two different 2Fe-2S clusters in which reducing equivalents necessary for catalysis are stored, a 40-kDa central domain containing a flavin adenine dinucleotide (FAD), and an 85-kDa C-terminal domain containing a molybdenum cofactor (MoCo) in which a substrate binding site is located (Garattini et al., 2008). Substrates are oxidized via Mo-OH by base-assisted hydroxylation at the MoCo center, the Mo being reduced from Mo(VI) to the MO(IV) state. MO(IV) is reoxidized via rapid one-electron transfer to the Fe-S cluster and further intramolecular electron transfer to FAD. FADH 2 is finally reoxidized by molecular oxygen to produce a superoxide anion and hydrogen peroxide via either a one-electron or a two-electron transfer. The enzyme catalyzes the nucleophilic, but not electrophilic, oxidation of a wide range of endogenous and e...

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Variation of Hepatic Methotrexate 7-Hydroxylase Activity in Animals and Humans

Cited by 23 publications

References 21 publications

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice

A Single Amino Acid Substitution Confers High Cinchonidine Oxidation Activity Comparable with That of Rabbit to Monkey Aldehyde Oxidase 1

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