The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 2004
Comparative StudyUDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver.
Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. However, the molecular basis for this phenomenon is currently unknown. We have previously shown that S-oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor R-oxazepam glucuronide is produced by multiple UGTs other than UGT2B15. ⋯ Donor gender also significantly influenced S-oxazepam glucuronidation with higher median activities in male (65 pmol/min/mg) compared with female (39 pmol/min/ mg) livers (p = 0.042). R-Oxazepam glucuronidation was not affected by either genotype or gender (p > 0.05). In conclusion, gender and D85Y genotype are identified as major determinants of S-oxazepam glucuronidation by human liver and may explain in part polymorphic oxazepam glucuronidation by human subjects.
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J. Pharmacol. Exp. Ther. · Aug 2004
Comparative StudyCyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues.
It has been suggested recently that cyclooxygenase-3, formed as a splice variant of cyclooxygenase-1, is the enzymatic target for acetaminophen. To investigate the relative roles of the putative three cyclooxygenase isoforms in different target tissues, we compared the inhibitory effects of acetaminophen, a cyclooxygenase-2-selective inhibitor; rofecoxib, a nonsteroid anti-inflammatory drug; naproxen; and a cyclooxygenase-1-selective inhibitor, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]. Prostanoid production by aorta, heart, lung, and whole blood was inhibited by all drugs tested with the order of potency SC560 > naproxen > acetaminophen >/= rofecoxib. ⋯ In conclusion, our studies indicate that cyclooxygenase-1 and cyclooxygenase-2 are the functional forms of the enzyme present in the rat tissues tested and that acetaminophen is not a selective inhibitor of "cyclooxygenase" activities in the central nervous system. This is consistent with the apparent impossibility for the expression of cyclooxygenase active protein from cyclooxygenase-3 mRNA in the rat. Also, our experiments show that the ability of rofecoxib to depress the circulating levels of prostaglandin I(2) is more readily associated with its ability to reduce production from the lung, heart, or brain than from arterial vessels.
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J. Pharmacol. Exp. Ther. · Aug 2004
Comparative StudyPoly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor.
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury during myocardial infarction. Because diabetes mellitus can substantially alter cellular signal transduction pathways, we have now investigated whether the PARP pathway also contributes to myocardial ischemia/reperfusion (MI/R) injury in diabetes mellitus in rodents. Myocardial ischemia/reperfusion in control and streptozotocin-diabetic rats was induced by transient ligation of the left anterior descending coronary artery. ⋯ In addition, there was a significant degree of mitochondrial-to-nuclear translocation of the cell death effector apoptosis-inducing factor (AIF) in myocardial infarction, which was blocked by pharmacological inhibition of PARP. The role of PARP in regulating AIF translocation in myocytes also was confirmed in an isolated perfused heart preparation. Overall, the current results demonstrate the importance of the PARP pathway in diabetic rats subjected to myocardial infarction and demonstrate the role of PARP in regulating AIF translocation in MI/R.
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J. Pharmacol. Exp. Ther. · Aug 2004
Comparative StudyDiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid), a novel, systemically available, and peripherally restricted Mu opioid agonist with antihyperalgesic activity: II. In vivo pharmacological characterization in the rat.
Mu opioid receptors are expressed throughout the central and peripheral nervous systems. Peripheral inflammation leads to an increase in mu receptor present on the peripheral terminals of primary sensory neurons. Activation of peripheral mu receptors produces potent antihyperalgesic effects in both humans and animals. ⋯ DiPOA also proved antihyperalgesic in a model of postsurgical pain with a maximum percent reversal of 85% 1 h postadministration at 30 mg/kg i.p. (the highest dose studied). DiPOA administered i.p. had no effect in the tail flick assay of acute pain (0.1-10 mg/kg), produced no ataxia as measured by latency to fall from an accelerating rotarod (3-30 mg/kg), and was not antihyperalgesic in the Seltzer model of neuropathic pain (1-10 mg/kg). This is the first report of a peripherally restricted, small-molecule mu opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically.
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J. Pharmacol. Exp. Ther. · Aug 2004
Comparative Study3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects.
3-[2-Cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074) is a novel, selective cannabinoid CB(1)/CB(2) receptor ligand (K(i) = 55.4, 48.3, and 45.5 nM at rat and human cannabinoid CB(1) and human CB(2) receptors, respectively), with partial agonist properties at these receptors in guanosine 5-[gamma(35)S]-thiophosphate triethyl-ammonium salt ([(35)S]GTPgammaS) binding assays. In rats, generalization of BAY 59-3074 to the cue induced by the cannabinoid CB(1) receptor agonist (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 38-7271) in a drug discrimination procedure, as well as its hypothermic and analgesic effects in a hot plate assay, were blocked by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). BAY 59-3074 (0.3-3 mg/kg, p.o.) induced antihyperalgesic and antiallodynic effects against thermal or mechanical stimuli in rat models of chronic neuropathic (chronic constriction injury, spared nerve injury, tibial nerve injury, and spinal nerve ligation models) and inflammatory pain (carrageenan and complete Freund's adjuvant models). ⋯ Uptitration from 1 to 32 mg/kg p.o. (doubling of daily dose every 4th day) prevented the occurrence of such side effects, whereas antihyperalgesic and antiallodynic efficacy was maintained/increased. No withdrawal symptoms were seen after abrupt withdrawal following 14 daily applications of 1 to 10 mg/kg p.o. It is concluded that BAY 59-3074 may offer a valuable therapeutic approach to treat diverse chronic pain conditions.