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Jallon, J. M., Risler, Y., & Iwatsubo, M. (1975). Beef liver L-Glutamate dehydrogenase mechanism: presteady state study of the catalytic reduction of 2.oxoglutarate by NADPH. Biochem Biophys Res Commun, 67(4), 1527–1536.
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Guo, G. L., Moffit, J. S., Nicol, C. J., Ward, J. M., Aleksunes, L. A., Slitt, A. L., et al. (2004). Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci, 82(2), 374–380.
Abstract: The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16alpha-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation.
Keywords: Acetaminophen/pharmacokinetics/*toxicity; Analgesics, Non-Narcotic/pharmacokinetics/*toxicity; Animals; Aryl Hydrocarbon Hydroxylases/biosynthesis; Biotransformation; Blotting, Northern; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Membrane Proteins; Mice; Mice, Knockout; Oxidoreductases, N-Demethylating/biosynthesis; Pregnenolone Carbonitrile/pharmacology; Receptors, Cytoplasmic and Nuclear/*drug effects; Receptors, Steroid/*drug effects; Sulfhydryl Compounds/metabolism
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Alexander, F., & Collett, R. A. (1974). Proceedings: Some observations on the pharmacokinetics of trimethoprim in the horse. Br J Pharmacol, 52(1), 142p.
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Machnik, M., Hegger, I., Kietzmann, M., Thevis, M., Guddat, S., & Schanzer, W. (2007). Pharmacokinetics of altrenogest in horses. J Vet Pharmacol Ther, 30(1), 86–90.
Abstract: The Federation Equestre Internationale has permitted the use of altrenogest in mares for the control of oestrus. However, altrenogest is also suspicious to misuse in competition horses for its potential anabolic effects and suppression of typical male behaviour, and thus is a controlled drug. To investigate the pharmacokinetics of altrenogest in horses we conducted an elimination study. Five oral doses of 44 mug/kg altrenogest were administered to 10 horses at a dose interval of 24 h. Following administration blood and urine samples were collected at appropriate intervals. Altrenogest concentrations were measured by liquid chromatography-tandem mass spectrometry. The plasma levels of altrenogest reached maximal concentrations of 23-75 ng/mL. Baseline values were achieved within 3 days after the final administration. Urine peak concentrations of total altrenogest ranged from 823 to 3895 ng/mL. Twelve days after the final administration concentrations were below the limit of detection (ca 2 ng/mL).
Keywords: Administration, Oral; Animals; Chromatography, Liquid/veterinary; Doping in Sports/prevention & control; Horses/*metabolism; Male; Mass Spectrometry/veterinary; Progesterone Congeners/administration & dosage/blood/*pharmacokinetics/urine; Reproducibility of Results; Substance Abuse Detection/veterinary; Trenbolone/administration & dosage/*analogs & derivatives/blood/pharmacokinetics/urine
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Hubbell, J. A. E., & Muir, W. W. (2006). Antagonism of detomidine sedation in the horse using intravenous tolazoline or atipamezole. Equine Vet J, 38(3), 238–241.
Abstract: REASONS FOR PERFORMING STUDY: The ability to shorten the duration of sedation would potentially improve safety and utility of detomidine. OBJECTIVES: To determine the effects of tolazoline and atipamezole after detomidine sedation. HYPOTHESIS: Administration of tolazoline or atipamezole would not affect detomidine sedation. METHODS: In a randomised, placebo-controlled, double-blind, descriptive study, detomidine (0.02 mg/kg bwt i.v.) was administered to 6 mature horses on 4 separate occasions. Twenty-five mins later, each horse received one of 4 treatments: Group 1 saline (0.9% i.v.) as a placebo control; Group 2 atipamezole (0.05 mg/kg bwt i.v.); Group 3 atipamezole (0.1 mg/kg bwt i.v.); and Group 4 tolazoline (4.0 mg/kg bwt i.v.). Sedation, muscle relaxation and ataxia were scored by 3 independent observers at 9 time points. Horses were led through an obstacle course at 7 time points. Course completion time was recorded and the ability of the horse to traverse the course was scored by 3 independent observers. Horses were videotaped before, during and after each trip through the obstacle course. RESULTS: Atipamezole and tolazoline administration incompletely antagonised the effects of detomidine, but the time course to recovery was shortened. CONCLUSIONS AND POTENTIAL RELEVANCE: Single bolus administration of atipamezole or tolazoline produced partial reversal of detomidine sedation and may be useful for minimising detomidine sedation.
Keywords: Animals; Behavior, Animal/drug effects/physiology; Dose-Response Relationship, Drug; Double-Blind Method; Horses/*physiology; Hypnotics and Sedatives/*antagonists & inhibitors; Imidazoles/*antagonists & inhibitors/*pharmacology; Infusions, Intravenous/veterinary; Kinetics; Safety; Tolazoline/*pharmacology; Videotape Recording
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Dirikolu, L., Lehner, A. F., Karpiesiuk, W., Hughes, C., Woods, W. E., Boyles, J., et al. (2003). Detection, quantification, metabolism, and behavioral effects of selegiline in horses. Vet Ther, 4(3), 257–268.
Abstract: Selegiline ([R]-[-]N,alpha-dimethyl-N-2- propynylphenethylamine or l-deprenyl), an irreversible inhibitor of monoamine oxidase, is a classic antidyskinetic and antiparkinsonian agent widely used in human medicine both as monotherapy and as an adjunct to levodopa therapy. Selegiline is classified by the Association of Racing Commissioners International (ARCI) as a class 2 agent, and is considered to have high abuse potential in racing horses. A highly sensitive LC/MS/MS quantitative analytical method has been developed for selegiline and its potential metabolites amphetamine and methamphetamine using commercially available deuterated analogs of these compounds as internal standards. After administering 40 mg of selegiline orally to two horses, relatively low (<60 ng/ml) concentrations of parent selegiline, amphetamine, and methamphetamine were recovered in urine samples. However, relatively high urinary concentrations of another selegiline metabolite were found, tentatively identified as N- desmethylselegiline. This metabolite was synthesized and found to be indistinguishable from the new metabolite recovered from horse urine, thereby confirming the chemical identity of the equine metabolite. Additionally, analysis of urine samples from four horses dosed with 50 mg of selegiline confirmed that N-desmethylselegiline is the major urinary metabolite of selegiline in horses. In related behavior studies, p.o. and i.v. administration of 30 mg of selegiline produced no significant changes in either locomotor activities or heart rates.
Keywords: Administration, Oral; Animals; Behavior, Animal/drug effects; Female; Horses/*metabolism; Mass Spectrometry/veterinary; Monoamine Oxidase Inhibitors/administration & dosage/blood/*pharmacokinetics/pharmacology/urine; Selegiline/administration & dosage/blood/*pharmacokinetics/pharmacology/urine; Substance Abuse Detection/veterinary
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Sukhomlinov, B. F., Korobov, V. N., Gonchar, M. V., Datsiuk, L. A., & Korzhev, V. A. (1987). [Comparative analysis of the peroxidase activity of myoglobins in mammals]. Zh Evol Biokhim Fiziol, 23(1), 37–41.
Abstract: Studies have been made on the peroxidase activity of metmyoglobins in animals from various ecological groups--the horse Equus caballus, cattle Bos taurus, beaver Castor fiber, otter Lutra lutra, mink Mustela vison and dog Canis familiaris. It was found that the level of this activity in diving animals depends on the duration of their diving, whereas in terrestrial species--on the strength of muscular contraction.
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Bykov, S., Lednev, I., Ianoul, A., Mikhonin, A., Munro, C., & Asher, S. A. (2005). Steady-state and transient ultraviolet resonance Raman spectrometer for the 193-270 nm spectral region. Appl Spectrosc, 59(12), 1541–1552.
Abstract: We describe a state-of-the-art tunable ultraviolet (UV) Raman spectrometer for the 193-270 nm spectral region. This instrument allows for steady-state and transient UV Raman measurements. We utilize a 5 kHz Ti-sapphire continuously tunable laser (approximately 20 ns pulse width) between 193 nm and 240 nm for steady-state measurements. For transient Raman measurements we utilize one Coherent Infinity YAG laser to generate nanosecond infrared (IR) pump laser pulses to generate a temperature jump (T-jump) and a second Coherent Infinity YAG laser that is frequency tripled and Raman shifted into the deep UV (204 nm) for transient UV Raman excitation. Numerous other UV excitation frequencies can be utilized for selective excitation of chromophoric groups for transient Raman measurements. We constructed a subtractive dispersion double monochromator to minimize stray light. We utilize a new charge-coupled device (CCD) camera that responds efficiently to UV light, as opposed to the previous CCD and photodiode detectors, which required intensifiers for detecting UV light. For the T-jump measurements we use a second camera to simultaneously acquire the Raman spectra of the water stretching bands (2500-4000 cm(-1)) whose band-shape and frequency report the sample temperature.
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Abbruzzetti, S., Viappiani, C., Sinibaldi, F., & Santucci, R. (2004). Kinetics of histidine dissociation from the heme Fe(III) in N-fragment (residues 1-56) of cytochrome c. Protein J, 23(8), 519–527.
Abstract: We have here investigated the dissociation kinetics of the His side chains axially ligated to the heme-iron in the ferric (1-56 residues) N-fragment of horse cyt c. The ligand deligation induced by acidic pH-jump occurs as a biexponential process with different pre-exponential factors, consistent with a structural heterogeneity in solution and the presence of two differently coordinated species. In analogy with GuHCl-denatured cyt c, our data indicate the presence in solution of two ferric forms of the N-fragment characterized by bis-His coordination, as summarized in the following scheme: His18-Fe(III)-His26 <==> His18-Fe(III)-His33. We have found that the pre-exponential factors depend on the extent of the pH-jump. This may be correlated with the different pKa values shown by His26 and His33; due to steric factors, His26 binds to the heme-Fe(III) less strongly than His33, as recently shown by studies on denatured cyt c. Interestingly, the two lifetimes are affected by temperature but not by the extent of the pH-jump. The lower pKa for the deligation reaction required the use of an improved laser pH-jump setup, capable of inducing changes in H+ concentration as large as 1 mM after the end of the laser pulse. For the ferric N-fragment, close activation entropy values have been determined for the two histidines coordinated to the iron; this result significantly differs from that for GuHCl-denatured cyt c, where largely different values of activation entropy were calculated. This underlines the role played by the missing segment (residues 57-104) peptide chain in discriminating deligation of the “nonnative” His from the sixth coordination position of the metal.
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Hirota, S., Suzuki, M., & Watanabe, Y. (2004). Hydrophobic effect of trityrosine on heme ligand exchange during folding of cytochrome c. Biochem Biophys Res Commun, 314(2), 452–458.
Abstract: Effect of a hydrophobic peptide on folding of oxidized cytochrome c (cyt c) is studied with trityrosine. Folding of cyt c was initiated by pH jump from 2.3 (acid-unfolded) to 4.2 (folded). The Soret band of the 2-ms transient absorption spectrum during folding decreased its intensity and red-shifted from 397 to 400 nm by interaction with trityrosine, whereas tyrosinol caused no significant effect. The change in the transient absorption spectrum by interaction with trityrosine was similar to that obtained with 100 mM imidazole, which showed that the population of the intermediate His/His coordinated species increased during folding of cyt c by interaction with trityrosine. The absorption change was biphasic, the fast phase (82+/-9s(-1)) corresponding to the transition from the His/H(2)O to the His/Met coordinated species, whereas the slow phase (24+/-3s(-1)) from His/His to His/Met. By addition of trityrosine, the relative ratio of the slow phase increased, due to increase of the His/His species at the initial stage of folding. According to the resonance Raman spectra of cyt c, the high-spin 6-coordinate and low-spin 6-coordinate species were dominated at pH 2.3 and 4.2, respectively, and these species were not affected by addition of trityrosine. These results demonstrated that the His/His species increased by interaction with trityrosine at the initial stage of cyt c folding, whereas the heme coordination structure was not affected by trityrosine when the protein was completely unfolded or folded. Hydrophobic peptides thus may be useful to study the effects of hydrophobic interactions on protein folding.
Keywords: Amino Acids/chemistry; Animals; Cytochromes c/*chemistry; Heme/*chemistry; Histidine/chemistry; Horses; Hydrogen-Ion Concentration; Kinetics; Ligands; Myocardium/chemistry; Peptides/chemistry; Protein Folding; Spectrophotometry; Spectrum Analysis, Raman; Tyrosine/*analogs & derivatives/*chemistry
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