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K F Tipton

Publications and source records attributed to K F Tipton.

At least 55 records · Page 3Linked to original sources
PubMed1998

Monoamine oxidases and related amine oxidases as phase I enzymes in the metabolism of xenobiotics.

To date most of the interest in oxidative metabolism of xenobiotics has been devoted to the role of the microsomal cytochrome P-450 system and to establish the basis for classifying and naming P450 enzymes. The contribution of amine oxidases to the metabolism of xenobiotics has been largely neglected, with the exception of the contribution of monoamine oxidases (MAOs) to the metabolism of exogenous tyramine and the studies of the "cheese effect" produced as the result of ingestion of large amounts of tyramine-containing foods under particular conditions. A review of the involvement of the mitochondrial MAOs in drug metabolism was published in 1988. Since that time, considerable additional evidence has appeared in the literature to support the contribution of MAOs to drug metabolism. In addition, the involvement of other amine oxidases in the metabolism of foreign compounds has been established. A second review on the contribution of amine oxidases to the metabolism of xenobiotics was therefore published in 1994. On an arbitrary basis, the heterogeneous class of amine oxidases can be divided into two types according to their prosthetic group: the flavineadenine dinucleotide (FAD)-dependent amine oxidases (Monoamine Oxidase and Polyamine Oxidase) and the amine oxidases not containing FAD (Semicarbazide-sensitive amine oxidases). In this overview, the contributions of these two types in xenobiotic metabolism are considered separately.

Animals↗
PubMed1998

The oxidation of dopamine and epinine by the two forms of monoamine oxidase from rat liver.

Information on the "in vitro" oxidation of epinine by monoamine oxidase (MAO) compared to dopamine is very poor. The aim of this work was to study the oxidative deamination of epinine and dopamine by rat liver MAO-A and MAO-B. The contributions of MAO-A and B to the metabolism of dopamine (55% and 45%, respectively) and epinine (70% and 30%, respectively) were similar. The results of this study show that epinine is a substrate for both forms of MAO in rat liver, although the contribution of MAO A to the deamination of this secondary amine appears to be slightly more important than that of MAO B.

Animals↗
PubMed1998

Studies on the time-dependent activation of microsomal semicarbazide-sensitive amine oxidase.

The semicarbazide-sensitive amine oxidase (SSAO) from bovine lung microsomes was activated in a temperature- and time-dependent process. This behaviour was observed when the enzyme was preincubated at 25 degrees C, 37 degrees C and 50 degrees C but not at 4 degrees C. This activation was only observed when benzylamine was used as substrate but not when methylamine, histamine or 2-phenylethylamine were used. The activation was independent of pH, ionic strength and the nature of the buffer used. At 37 degrees C the specific activity had risen to a value that was about 7 times higher than that of the starting material after 120 min. This process affected only the maximum velocity of the reaction with the Km value remaining essentially unchanged. Treatment of SSAO with phospholipases and detergents did not affect this behaviour. Incubation of the enzyme with serine proteases, metal chelating agents, reducing agents or protease inhibitors, had no effect on the activation. The fact that both forms of the enzyme (activated and non-activated), showed the same Mr values on gel filtration chromatography excluded the possibility of an enzyme aggregation and/or degradation being involved in this process.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Studies on the behaviour of semicarbazide-sensitive amine oxidase in Sprague-Dawley rats treated with the monoamine oxidase inhibitor tranylcypromine.

The possibility that increased levels of the activity of the semicarbazide-sensitive amine oxidase (SSAO) might, to some extent, compensate for the loss of monoamine oxidase (MAO) activity in the atypical form of Norrie Disease, was examined using the rat as a model. Long-term treatment with the MAO inhibitor tranylcypromine (1 mg/kg/day) resulted in sustained inhibition of MAO-A and MAO-B activities in liver and brain. After one week, the SSAO activity in heart had increased by 79% above the control levels. This increase was maintained for 3 weeks. Since such alterations might result from enzyme induction, the turnover of the enzyme was studied in cultured cells from rat aortic smooth muscle. The time-course of recovery of enzyme activity following irreversible inhibition by MDL 72145 corresponded to a half-life of approximately 6 days for this process.

Allylamine↗
PubMed1997

The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence.

This review represents an update of the nomenclature system for the UDP glucuronosyltransferase gene superfamily, which is based on divergent evolution. Since the previous review in 1991, sequences of many related UDP glycosyltransferases from lower organisms have appeared in the database, which expand our database considerably. At latest count, in animals, yeast, plants and bacteria there are 110 distinct cDNAs/genes whose protein products all contain a characteristic 'signature sequence' and, thus, are regarded as members of the same superfamily. Comparison of a relatedness tree of proteins leads to the definition of 33 families. It should be emphasized that at least six cloned UDP-GlcNAc N-acetylglucosaminyltransferases are not sufficiently homologous to be included as members of this superfamily and may represent an example of convergent evolution. For naming each gene, it is recommended that the root symbol UGT for human (Ugt for mouse and Drosophila), denoting 'UDP glycosyltransferase,' be followed by an Arabic number representing the family, a letter designating the subfamily, and an Arabic numeral denoting the individual gene within the family or subfamily, e.g. 'human UGT2B4' and 'mouse Ugt2b5'. We recommend the name 'UDP glycosyltransferase' because many of the proteins do not preferentially use UDP glucuronic acid, or their nucleotide sugar preference is unknown. Whereas the gene is italicized, the corresponding cDNA, transcript, protein and enzyme activity should be written with upper-case letters and without italics, e.g. 'human or mouse UGT1A1.' The UGT1 gene (spanning > 500 kb) contains at least 12 promoters/first exons, which can be spliced and joined with common exons 2 through 5, leading to different N-terminal halves but identical C-terminal halves of the gene products; in this scheme each first exon is regarded as a distinct gene (e.g. UGT1A1, UGT1A2, ... UGT1A12). When an orthologous gene between species cannot be identified with certainty, as occurs in the UGT2B subfamily, sequential naming of the genes is being carried out chronologically as they become characterized. We suggest that the Human Gene Nomenclature Guidelines (http://www.gene.acl.ac.uk/nomenclature/guidelines.html++ +) be used for all species other than the mouse and Drosophila. Thirty published human UGT1A1 mutant alleles responsible for clinical hyperbilirubinemias are listed herein, and given numbers following an asterisk (e.g. UGT1A1*30) consistent with the Human Gene Nomenclature Guidelines. It is anticipated that this UGT gene nomenclature system will require updating on a regular basis.

Amino Acid Sequence↗
PubMed1997

Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle.

We examined whether chronic stimulation of red and white rat muscles increased the concentrations of the monocarboxylate transporter MCT1. Red and white tibialis anterior (RTA and WTA, respectively) and extensor digitorum longus (EDL) muscles were chronically stimulated via the peroneal nerve for 7 days. Stimulated and contralateral control muscles were examined for MCT1 content, L-lactate uptake, lactate dehydrogenase (LDH) isoforms, and muscle fiber composition. MCT1 was 1.5 times greater in stimulated RTA, 3 times greater in stimulated WTA, and 1.9 times greater in stimulated EDL compared with respective control muscles (P < 0.05). L-Lactate uptake increased in all stimulated muscles (P < 0.05), and this was highly correlated with the increase in MCT1 (r = 0.96). The heart-type LDH (H-LDH) subunits also increased in all stimulated muscles (P < 0.05). The H-LDH subunits correlated highly with MCT1 in the muscles (r = 0.83). There was no change in muscle-type LDH subunits (P > 0.05). There were negligible alterations in muscle fiber composition in the stimulated muscles, suggesting that the increase in MCT1 was independent of changes in muscle fiber composition. These studies are the first to demonstrate that chronic muscle contraction increases MCT1 concentrations in both red and white skeletal muscles.

Animals↗
PubMed1996

Inhibition of bovine lung semicarbazide-sensitive amine oxidase (SSAO) by some hydrazine derivatives.

Microsomal semicarbazide-sensitive amine oxidase (SSAO) from bovine lung was shown to be inhibited by a number of hydrazine derivatives, but the mechanisms of inhibition were found to differ. Hydralazine behaved as an irreversible and partially time-dependent inhibitor with an IC50 value of 1 microM under the conditions used. Phenylhydrazine was found to be a potent irreversible inhibitor of SSAO (IC50 30 nM). Semicarbazide behaved as a specific irreversible inhibitor (active-site-directed irreversible inhibitor) in first forming a non-covalent enzyme-semicarbazide complex (with a Ki value of 85 microM), which then reacted to give an irreversibly inhibited enzyme species in a reaction defined by the first-order rate constant k2 = 0.065 min-1. Phenelzine behaved as a reversible inhibitor, but dialysis at 37 degrees C was found to be necessary to obtain full recovery of enzyme activity. The dependence of inhibition on phenelzine concentration was complex and consistent with multiple binding sites for this inhibitor. This diversity in the action of a family of compounds with the same functional group must be taken into account in attempts to design more specific inhibitors of this enzyme.

Amine Oxidase (Copper-Containing)↗
PubMed1996

Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine.

The catecholaminergic neurotoxin 6-hydroxydopamine causes parkinsonian symptoms in animals and it has been proposed that reactive oxygen species and oxidative stress, enhanced by iron, may play a key role in its toxicity. The present results demonstrate that 6-hydroxydopamine reversibly inhibits complex I (NADH dehydrogenase) of brain mitochondrial respiratory chain in isolated mitochondria. 6-Hydroxydopamine itself, rather than its oxidative products, was responsible for the inhibition. Iron (III) did not enhance inhibition but decreased it by stimulating the nonenzyme oxidation of 6-hydroxydopamine. Inhibition was potentiated to some extent by calcium ion. Desferrioxamine protected complex I activity against the inhibition, but it was not due to its chelator or antioxidative properties. Desferrioxamine was also shown to activate NADH dehydrogenase in the absence of 6-hydroxydopamine. Activation of mitochondrial respiration by desferrioxamine may contribute to the enhanced neuron survival in the presence of desferrioxamine in some neurodegenerative conditions.

Animals↗
PubMed1995

Species differences in the interactions of the anticonvulsant milacemide and some analogues with monoamine oxidase-B.

Oxidation of the anticonvulsant drug milacemide [2-n-(pentylamino)acetamide] by monoamine oxidase-B (MAO-B) has been reported to be important in terminating its activity. Comparison of the oxidation of this compound by MAO-B preparations from ox and rat liver showed the former enzyme to have a significantly higher Km value towards this substrate. In keeping with this, the Ki values for milacemide acting as a competitive inhibitor of these enzymes showed it to have a lower affinity for ox liver MAO-B. Comparative studies on the time-dependent inhibition of the two enzymes also showed a lower sensitivity of that from the ox liver. Studies with a series of analogues involving replacement of pentylamino group of milacemide showed marked differences between the sensitivities of the two enzymes. The largest differences were shown by the compound 2(4-(3-chlorobenzoxy)phenethylamino)acetamide which gave IC50 values of 0.051 +/- 0.008 and 4.1 +/- 0.8 microM with the rat and ox enzymes, respectively, when activities were assayed without prior enzyme-inhibitor preincubation. When the enzyme and inhibitor were incubated for 60 min at 37 degrees before assay these values fell to 0.027 +/- 0.002 and 3.5 +/- 0.4 microM, respectively. These marked differences prompted a study of the inhibition of MAO-A and MAO-B from human liver and brain, mouse brain and rat brain as well as MAO-B from ox liver by milacemide and alpha-methylmilacemide. There were no significant differences in the sensitivities of any of the mitochondrial MAO-A preparations studied towards these compounds. However, MAO-B from human brain and liver mitochondrial resembled that from ox liver in being less sensitive to inhibition than the rat and mouse enzymes. Purification of the ox liver MAO-B did not significantly affect its interactions with milacemide and alpha-methylmilacemide. The marked species differences reported here raise questions concerning the validity of rodent model systems, that have frequently been used for assessing the in vivo and in vitro actions of milacemide and its analogues, for the situation in the human.

Acetamides↗