Skip to content. Skip to navigation
Sections
Personal tools
You are here: Home
Featured Journal
Navigation
Site Search
 
Search only the current folder (and sub-folders)
Log in


Forgot your password?
New user?
Check out our New Publishers' Select for Free Articles
Journal Search

Biochemical Pharmacology (v.76, #7)


The pharmacology and molecular mechanisms underlying temperature regulation and torpor by Steven J. Swoap (pp. 817-824).
The ability to enter a hypometabolic state upon restriction of caloric intake is pivotal for animal survival: balancing the energy budget in endotherms can be a real struggle when food is not available and/or the demand for heat production to maintain homeothermy becomes excessive. Bouts of torpor, characterized by metabolic rates well below a basal metabolic rate and core body temperatures that may be just a few degrees above the ambient temperature, are utilized among many organisms across the animal kingdom, including those that could be described as typical laboratory animals, like the mouse or hamster. Daily heterotherms, which are the focus of this commentary, enter shallow torpor bouts and do so usually under acute food shortage conditions and a relatively cool environment. Due to their small size, the body temperature of these animals is very responsive to food deprivation, pharmacological inhibition of metabolic rate, and cardiovascular depressants. This commentary examines recent developments concerning the neuroendocrine mechanisms in place that may mediate fasting-induced torpor in daily heterotherms. Further this commentary highlights pharmacological induction of hypothermia in small mammals.

Keywords: Hibernation; Torpor; Metabolism; Leptin; Mouse


Bisphosphonates activate the 5-fluorouracil/uracil phosphoribosyltransferase activity present in Saccharomyces cerevisiae cell extracts by Francisco J. Pérez-Zúñiga; María A. Günther Sillero; Antonio Sillero (pp. 825-830).
Most of the effects described for bisphosphonates (pC(R1)(R2)p) are related, directly or indirectly with a pyrophosphate moiety. Bisphosphonates are (i) analogs of pyrophosphate in the synthesis of ATP derivatives (AppC(R1)(R2)p) catalyzed by ligases and (ii) inhibitors of enzymes of the mevalonate pathway with substrates containing a terminal pyrophosphate. Searching for the role of bisphosphonates on other reactions involving pyrophosphate, we explored their effect on a phosphoribosyltransferase activity, present in Saccharomyces cerevisiae cell extracts, using 5-fluorouracil or uracil as substrates. Unexpectedly, bisphosphonates increased the initial rate of synthesis of 5-FUMP (from 5-fluorouracil and phosphoribosylpyrophosphate): etidronate (2.8±0.3 times); pamidronate (2.6±0.4 times); alendronate (2.5±0.6 times) and clodronate (2.0±0.1 times). Similar values for the synthesis of UMP (from uracil and phosphoribosylpyrophosphate) were obtained in the presence of bisphosphonates. The values of the activation constants determined for alendronate and clodronate for the synthesis of UMP were 0.05±0.02mM and 0.32±0.22mM, respectively. These results raise the possibility that bisphosphonates enhance the effect of 5-fluorouracil (or other uracil prodrugs) in the treatment of bone tumors or bone tumor metastases.

Keywords: Abbreviations; AppC(R; 1; )(R; 2; )p; adenosine 5′-triphosphate derivative of any bisphosphonate; AppCCl; 2; p; adenosine 5′-(β,γ-dichloromethylene)triphosphate; AppCH; 2; p; adenosine 5′-(β,γ-methylene)triphosphate; Apppl; (triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester); BP(s); bisphosphonate(s); FU or 5-FU; 5-fluorouracil; N-BP; a bisphosphonate containing nitrogen; non-N-BP; a bisphosphonate not containing nitrogen; pC(OH)(CH; 2; –CH; 2; –CH; 2; –NH; 3; )p; alendronate or 4-amino-1-hydroxybutylidene-1,1-bisphosphonate; pC(OH)(CH; 2; –CH; 2; –NH; 3; )p; pamidronate or 3-amino-1-hydroxypropylidene-1,1-bisphosphonate; pC(OH)(CH; 3; )p (HEBP); etidronate or ethane-1-hydroxy-1,1-bisphosphonate or hydroxyethylidenebisphosphonate; pCCl; 2; p (Cl; 2; MBP); clodronate or methane-1-dichloro-1,1-bisphosphonate or dichloromethylenebisphosphonate; pCH; 2; p; methylenebisphosphonate or methyleneBP; PRPP; 5-phospho-α-; d; -ribose 1-pyrophosphate; R; f; the value traveled by the solvent front divided by the distance traveled by a given compound; TLC; thin layer chromatographyBisphosphonates; Bone; Tumor; Osteoclasts; Osteoporosis; Phosphoribosyltransferase


Virus entry inhibition by chlorite-oxidized oxyamylose versus induction of antiviral interferon by poly(I:C) by Sandra Li; Erik Martens; Chris Dillen; Philippe E. Van den Steen; Ghislain Opdenakker (pp. 831-840).
Unlike polyribonucleotides, such as poly(I:C), chlorite-oxidized oxyamylose (COAM) has been poorly characterized as a polyanionic antiviral. COAM possesses a controversial interferon (IFN)-inducing capacity and its mechanism of action has not been elucidated. In this study, COAM was biochemically characterized and fractionated according to molecular mass. In comparison with a strong IFN induction and upregulation of the helicase RIG-I and MDA-5 mRNAs by poly(I:C), COAM did not enhance IFN-α or -β and IFN-inducible RNA helicases in mouse fibroblastoid cells. Instead, COAM inhibited virus entry by blocking the attachment to the cells. These results suggest that COAM can alter the outcome of infection, not by IFN induction and in turn modifying the cellular antiviral state, but through inhibition of virus entry into cells.

Keywords: COAM; Polyanion; Polysaccharide; Antiviral; Entry inhibition; Interferon


Dexamethasone inhibits basic fibroblast growth factor-stimulated gastric epithelial cell proliferation by Jiing-Chyuan Luo; Hsiao-Yi Lin; Ching-Liang Lu; Lung-Yao Wang; Full-Young Chang; Han-Chieh Lin; Yi-Chen Huang; Ka-Man Ng; Chin-Wen Chi; Shou-Dong Lee (pp. 841-849).
Basic fibroblast growth factor (bFGF) is essential for gastric ulcer healing, whereas glucocorticoids delay gastric ulcer healing. We found that dexamethasone inhibited bFGF-stimulated rat gastric epithelial RGM-1 cells proliferation and attempted to elucidate the possible mechanistic pathway. Flowcytometry was used to determine cell proliferation. Western blot and RT-PCR were performed to evaluate changes in signaling pathways. Results showed that bFGF significantly increased mRNA expression of FGF receptor (FGFR)1 and FGFR2 at 10min and increased expression of phosphorylated extracellular signal-regulated kinase (pERK1/pERK2) but not phosphorylated p38 mitogen-activated protein kinase (MAPK) or phosphorylated phosphatidylinositol 3-kinase (PI3K) within 30min. This was followed by an increase of cyclooxygenase (COX)-2 mRNA and protein expression at 30 and 240min, respectively. Mitogen-activated protein kinase kinase (MEK) inhibitor-PD98059 (10−5M) markedly suppressed bFGF-stimulated COX-2 expression and cell proliferation, but neither p38 MAPK inhibitor-SB203580 nor PI3K inhibitor-Wortmannin had any effect. Dexamethasone (10−6M) substantially reduced bFGF-stimulated ERK activation at 10min, COX-2 mRNA and protein expression at 30 and 240min, respectively, and prostaglandin E2 synthesis at 8h. Dexamethasone (10−6M) also significantly decreased mRNA expression of FGFR1 and FGFR2 at basal and bFGF-stimulated conditions at 10min. This study indicated that bFGF-stimulated gastric epithelial RGM-1 cells proliferation via up-regulating FGFR1 and FGFR2, activating ERK1/ERK2 signal transduction pathway and COX-2 pathway. Dexamethasone significantly suppresses bFGF-stimulated RGM-1 cells proliferation in part via down-regulation of FGFR1/FGFR2, then decreasing bFGF-stimulated activation of ERK1/ERK2, followed by inhibition of COX-2 activation, and finally DNA synthesis.

Keywords: bFGF; COX; Dexamethasone; ERK1/ERK2; Proliferation


Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84) by I.S. Haslam; K. Jones; T. Coleman; N.L. Simmons (pp. 850-861).
Intestinal induction of Pgp is known to limit the oral availability of certain drug compounds and give rise to detrimental drug–drug interactions. We have investigated the induction of P-glycoprotein (Pgp; MDR1) activity in a human intestinal epithelial cell line (T84) following pre-exposure to a panel of drug compounds, reported to be Pgp substrates, inhibitors or inducers.Human MDR1-transfected MDCKII epithelial monolayers were used to assess Pgp substrate interactions and inhibition of digoxin secretion by the selected drug compounds. The T84 cell line was used to assess induction of Pgp-mediated digoxin secretion following pre-exposure to the same compounds. Changes in gene expression (MDR1, MRP2, PXR and CAR) were determined by quantitative RT-PCR. Net transepithelial digoxin secretion was increased (1.3 fold, n=6, P<0.05) following pre-exposure to the PXR activator hyperforin (100nM, 72h), as was MDR1 mRNA expression (3.0 fold, n=4, P<0.05). A number of Pgp substrates (quinidine, amprenavir, irinotecan, topotecan, atorvastatin and erythromycin) induced net digoxin secretion, as did the non-Pgp substrate artemisinin. Various non-Pgp substrates demonstrated inhibition of digoxin secretion (verapamil, mifepristone, clotrimazole, mevastatin, diltiazem and isradipine) but did not induce Pgp-mediated digoxin secretion. Of the compounds that increased Pgp secretion, quinidine, topotecan, atorvastatin and amprenavir pre-exposure also elevated MDR1 mRNA levels, whereas erythromycin, irinotecan and artemisinin displayed no change in transcript levels. This indicates possible post-translational regulation of digoxin secretion. Finally, a strong correlation between drug modulation of MRP2 and PXR mRNA expression levels was evident.

Keywords: Intestine; T84; Pgp; MDR1; Induction


Celecoxib inhibits 5-lipoxygenase by Thorsten J. Maier; Lars Tausch; Michael Hoernig; Ovidiu Coste; Ronald Schmidt; Carlo Angioni; Julia Metzner; Sabine Groesch; Carlo Pergola; Dieter Steinhilber; Oliver Werz; Gerd Geisslinger (pp. 862-872).
Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used in the therapy of inflammatory and painful conditions. Various COX-2-independent pharmacological effects, such as a chemo-preventive and tumor-regressive activity have been suggested, but the respective non-COX-2 targets of celecoxib are still a matter of research. We now demonstrate that celecoxib inhibits 5-lipoxygenase (5-LO), a key enzyme in leukotriene (LT) biosynthesis. Celecoxib suppressed 5-LO product formation in ionophore A23187-activated human polymorphonuclear leukocytes (IC50≈8μM). Similarly, celecoxib inhibited LTB4 formation in human whole blood (IC50≈27.3μM). Direct interference of 5-LO with celecoxib was visualized by inhibition of enzyme catalysis both in cell homogenates and with purified 5-LO (IC50≈23.4 and 24.9μM, respectively). Related lipoxygenases (12-LO and 15-LO) were not affected by celecoxib. Other COX-2 inhibitors (etoricoxib and rofecoxib) or unselective NSAIDs (non-steroidal anti-inflammatory drugs, diclofenac) failed to inhibit 5-LO. In rats which received celecoxib (i.p.), the blood LTB4 levels were dose-dependently reduced with an ED50 value ≈35.2mg/kg. Together, celecoxib is a direct inhibitor of 5-LO in vitro and in vivo. These findings provide a potential molecular basis for some of the described COX-2-independent pharmacological effects of celecoxib.

Keywords: Abbreviations; AA; arachidonic acid; COX; cyclooxygenase; cPLA; 2; -alpha; cytosolic phospholipase A; 2; -alpha; FAP; familial adenomatous polyposis; FLAP; 5-lipoxygenase-activating protein; 5-HETE; 5(; S; )-hydroxy-8,11,14-; cis; -6-; trans; -eicosatetraenoic acid; 12-HETE; 12(; S; )-hydroxy-5,8-; cis; -10-; trans; -14-; cis; -eicosatetraenoic acid; 15-HETE; 15(; S; )-hydroxy-5,8,11-; cis; -13-; trans; -eicosatetraenoic acid; LC–MS/MS; liquid chromatography coupled with tandem mass spectrometry; 5-LO; 5-lipoxygenase; LT; leukotriene; NSAID; non-steroidal anti-inflammatory drug; PGE; 2; prostaglandin E; 2; PMNL; polymorphonuclear leukocytesNSAIDs; Leukotriene; Cyclooxygenase-2; Leukocytes; Whole blood assay


Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer by Christophe Blanquart; Josepha Achi; Tarik Issad (pp. 873-883).
The insulin receptor (IR) is composed of two α-chains that bind ligands and two β-chains that possess an intracellular tyrosine kinase activity. The IR is expressed in cells as two isoforms containing or not exon 11 (IRB and IRA, respectively). Several mRNA studies have demonstrated that the two isoforms are co-expressed in different tissues and in several cancer cells. IRA/IRB hybrid receptors, constituting of an αβ-chain from IRA and an αβ-chain from IRB, are likely to occur in cells co-expressing both isoforms, but their study has been hampered by the lack of specific tools. In previous work, we used BRET to study IR and IGF1R homodimers and heterodimers. Here, we have used BRET to characterize IRA/IRB hybrids. BRET saturation experiments showed that IRA/IRB hybrids are randomly formed in cells. Moreover, by co-transfecting HEK-293 cells with a luciferase-tagged kinase-dead version of one isoform and a wild-type untagged version of the other isoform, we showed that IRA/IRB hybrids can recruit, upon ligand stimulation, a YFP-tagged intracellular partner. Finally, using BRET, we have studied ligand-induced conformational changes within IRA/IRB hybrids. Dose-response experiments showed that hybrid receptors bind IGF-2 with the same affinity than IRA homodimers, whereas they bind IGF-1 with a lower affinity. Altogether, our data indicate that IRA/IRB hybrid receptors can form in cells co-expressing both IR isoforms, that they are capable of recruiting intracellular partners upon ligand stimulation, and that they have pharmacological properties more similar to those of IRA than those of IRB homodimers with regards to IGF-2.

Keywords: Insulin receptor isoforms; Insulin-like growth factor; Diabetes; Cancer; BRET


Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets by Deena Waddleton; Weizhen Wu; Yue Feng; Chris Thompson; Michael Wu; Yun-Ping Zhou; Andrew Howard; Nancy Thornberry; Jing Li; Joseph A. Mancini (pp. 884-893).
cAMP is a key modulator for glucose-dependent insulin secretion (GDIS). Members of the phosphodiesterase (PDEs) gene family regulate intracellular levels of cAMP by hydrolyzing cAMP to the corresponding inactive 5′AMP derivative. These studies examined the expression and function of all 18 cAMP-specific PDEs in the rat insulinoma derived INS-1 (832/13) cell and isolated rat islets using quantitative PCR and siRNA-mediated gene-specific knockdown. PDE1C, PDE3B, PDE4C, PDE8B, PDE10A, and PDE11A were significantly expressed in rat islets and INS-1 (832/13) cells at the mRNA level. PDE1C, PDE10A and PDE11A were also expressed in brain, along with PDE3B, PDE4C and PDE8B which were also highly expressed in liver, and PDE3B was present in adipose tissue and PDE4C in skeletal muscle. siRNA mediated knockdown of PDE1C, PDE3B, PDE8B and PDE4C, but not PDE10A and PDE11A, significantly enhanced GDIS in rat INS-1 (832/13) cells. Also, selective inhibitors of PDE3 (trequinsin) and PDE4 (roflumilast and L-826,141) significantly augmented GDIS in both INS-1 (832/13) cells and rat islets. The combination of PDE3 and PDE4 selective inhibitors demonstrate that these enzymes comprise a significant proportion of the cAMP metabolizing activity in INS-1 cells and rat islets.

Keywords: PDE; cAMP; Pancreatic islets; Type 2 diabetes


Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1 by Tomoko Sato; Satohiro Masuda; Atsushi Yonezawa; Yuko Tanihara; Toshiya Katsura; Ken-ichi Inui (pp. 894-903).
To clarify the transcellular transport of organic cations via basolateral and apical transporters, we established double-transfected Madin–Darby canine kidney (MDCK) cells expressing both human organic cation transporter hOCT1 and hMATE1 (MDCK-hOCT1/hMATE1), and hOCT2 and hMATE1 (MDCK-hOCT2/hMATE1) as models of human hepatocytes and renal epithelial cells, respectively. Using the specific antibodies, hOCT1 and hMATE1 or hOCT2 and hMATE1 were found to be localized in the basolateral and apical membranes of MDCK-hOCT1/hMATE1 or MDCK-hOCT2/hMATE1 cells, respectively. A representative substrate, [14C]tetraethylammonium, was transported unidirectionally from the basolateral to apical side in these double transfectants. The optimal pH was showed to be 6.5 for the transcellular transport of [14C]tetraethylammonium, when the pH of the incubation medium on the apical side was varied from 5.5 to 8.5. The basolateral-to-apical transport also decreased in the presence of 10mM 1-methyl-4-phenylpyridinium or 1mM levofloxacin on the basolateral side of both double transfectants. In MDCK-hOCT2/hMATE1 cell monolayers, but not in MDCK-hOCT1/hMATE1 cell monolayers, the accumulation of [14C]tetraethylammonium was decreased in the presence of 10mM 1-methyl-4-phenylpyridinium, but significantly increased in the presence of 1mM levofloxacin. The uptake of [14C]tetraethylammonium, [3H]1-methyl-4-phenylpyridinium, [14C]metformin and [3H]cimetidine, but not of [14C]procainamide and [3H]quinidine, by HEK293 cells was stimulated by expression of the hOCT1, hOCT2 or hMATE1 compared to control cells. However, transcellular transport of [14C]procainamide and [3H]quinidine was clearly observed in both double-transfectants. These cells could be useful for examining the routes by which compounds are eliminated, or predicting transporter-mediated drug interaction.

Keywords: Renal tubular transport; Vectorial transport; OCT1; OCT2; MATE1; Quinidine


Complementary DNA cloning, functional expression and characterization of a novel cytochrome P450, CYP2D50, from equine liver by H.K. DiMaio Knych; S.D. Stanley (pp. 904-911).
Members of the CYP2D family constitute only about 2–4% of total hepatic CYP450s, however, they are responsible for the metabolism of 20–25% of commonly prescribed therapeutic compounds. CYP2D enzymes have been identified in a number of different species. However, vast differences in the metabolic activity of these enzymes have been well documented. In the horse, the presence of a member of the CYP2D family has been suggested from studies with equine liver microsomes, however its presence has not been definitively proven. In this study a cDNA encoding a novel CYP2D enzyme (CYP2D50) was cloned from equine liver and expressed in a baculovirus expression system. The nucleotide sequence of CYP2D50 was highly homologous to that of human CYP2D6 and therefore the activity of the enzyme was characterized using dextromethorphan and debrisoquine, two isoform selective substrates for the human orthologue. CYP2D50 displayed optimal catalytic activity with dextromethorphan using molar ratios of CYP2D50 to NADPH CYP450 reductase of 1:15. Although CYP2D50 and CYP2D6 shared significant sequence homology, there were striking differences in the catalytic activity between the two enzymes. CYP2D50 dextromethorphan- O-demethylase activity was nearly 180-fold slower than the human counterpart, CYP2D6. Similarly, rates of formation of 4-hydroxydebrisoquine activity were 50-fold slower for CYP2D50 compared to CYP2D6. The results of this study demonstrate substantial interspecies variability in metabolism of substrates by CYP2D orthologues in the horse and human and support the need to fully characterize this enzyme system in equids.

Keywords: CYP450; Horse; CYP2D; Dextromethorphan; Debrisoquine; Phase I metabolism


A new chemical tool (C0036E08) supports the role of adenosine A2B receptors in mediating human mast cell activation by Montserrat Buceta; Eduardo Domínguez; Marián Castro; José Brea; David Álvarez; Javier Barcala; Luis Valdés; Pedro Álvarez-Calderón; Fernando Domínguez; Bernat Vidal; Jose Luis Díaz; Montse Miralpeix; Jorge Beleta; María Isabel Cadavid; María Isabel Loza (pp. 912-921).
Asthma is a chronic inflammatory disease of the airways that involves many cell types, amongst which mast cells are known to be important. Adenosine, a potent bronchoconstricting agent, exerts its ability to modulate adenosine receptors of mast cells thereby potentiating derived mediator release, histamine being one of the first mediators to be released. The heterogeneity of sources of mast cells and the lack of highly potent ligands selective for the different adenosine receptor subtypes have been important hurdles in this area of research. In the present study we describe compound C0036E08, a novel ligand that has high affinity (p Ki 8.46) for adenosine A2B receptors, being 9 times, 1412 times and 3090 times more selective for A2B receptors than for A1, A2A and A3 receptors, respectively. Compound C0036E08 showed antagonist activity at recombinant and native adenosine receptors, and it was able to fully block NECA-induced histamine release in freshly isolated mast cells from human bronchoalveolar fluid. C0036E08 has been shown to be a valuable tool for the identification of adenosine A2B receptors as the adenosine receptors responsible for the NECA-induced response in human mast cells. Considering the increasing interest of A2B receptors as a therapeutic target in asthma, this chemical tool might provide a base for the development of new anti-asthmatic drugs.

Keywords: Abbreviations; AMP; adenosine 5′monophosphate; BALF; bronchoalveolar fluid; CGS15943; 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine; GM-CSF; granulocyte macrophage-colony stimulating factor; DPCPX; 1,3-dipropyl-8-cyclopentylxanthine; FceRI; high-affinity human IgE receptors; HMC; human mast cells; IgE; immunoglobulin E; IL; interleukin; IFN-γ; interferon γ; MRS; 1220 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline; MRS; 1754 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(; n; -propyl)xanthine; NECA; 5′-; N; -ethylcarboxamide-adenosine; PCA; perchloric acid; R-PIA; R(−) N6-(2-phenylisopropyl)-adenosine; SCH-58261; 5-amino-2-(2-furyl)-7-phenyilethyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; 8-SPT; 8-(; p; -sulfophenyl)-theophylline; TNF-α; tumor necrosis factor-alpha; XAC; 8-[-4-[[[[(2-aminoethyl)-amino]carbonyl]ethyl]oxy]phenyl]-1,3-dipropylxanthine; ZM241385; 4-(2-[7-amino-2-[furyl]-[1,2,4]triazolo[2,3-a]{1,3,5}triazin-5yl-amino]ethyl)phenolA; 2B; adenosine receptor; Mast cells; Asthma; Human bronchoalveolar fluid; Histamine


New insights into generalized hepatoprotective effects of oleanolic acid: Key roles of metallothionein and Nrf2 induction by Jie Liu; Qin Wu; Yuan-Fu Lu; Jingbo Pi (pp. 922-928).
Oleanolic acid (OA) is a natural triperpenoid that protects against a variety of hepatotoxicants such as carbon tetrachloride, cadmium, acetaminophen, and bromobenzene. To gain insight into the molecular mechanisms of this generalized hepatoprotection, genomic analysis was performed on mouse and rat livers after OA treatment. Mice and rats were given OA at a hepatoprotective dose (50μmol/kg, s.c., daily for 4 days) and hepatic RNA was isolated, purified, and subjected to gene expression analysis. OA treatment produced changes in 5% of the genes on custom-designed mouse liver array and rat toxicology-II array. Changes in key gene expressions were further analyzed by real-time RT-PCR. OA treatment dramatically increased expression of hepatic metallothionein ( Mt), and increased the expression of the nuclear factor E2-related factor 2 ( Nrf2), NAD(P)H:quinone oxidoreductase 1 ( Nqo1), heme oxygenase-1 ( Hmox1), and glutamate–cysteine ligases ( Gclc and Gclm). OA treatment also increased the expression of genes related to cell proliferation and suppressed the expression of several cytochrome P450 genes possibly to switch cellular metabolic energy to an acute-phase response. Hepatic MT protein was increased 60- and 15-fold in mice and rats, respectively, together with a 30% increase in mouse liver zinc. These gene expression changes, particularly the dramatic induction of MT and the Nrf2 signaling, occur with hepatoprotection doses of OA, and likely are important in the generalized protective effects of OA against hepatotoxicants.

Keywords: Oleanolic acid; Triterpenoid; Hepatoprotection; Gene expression; Metallothionein; Nrf2 signaling


Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers by Joshua E. Muscat; Brian Pittman; Wayne Kleinman; Philip Lazarus; Steven D. Stellman; John P. Richie Jr. (pp. 929-937).
The lower incidence rate of transitional cell carcinoma of the urinary bladder in blacks than in whites may be due to racial differences in the catalytic activity of enzymes that metabolize carcinogenic arylamines in tobacco smoke. To examine this, we compared cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 activities (NAT2) in black and white smokers using urinary caffeine metabolites as a probe for enzyme activity in a community-based study of 165 black and 183 white cigarette smokers. The paraxanthine (1,7-dimethylxanthine, 17X)/caffeine (trimethylxanthine, 137X) ratio or [17X+1,7-dimethyluric acid (17U)]/137X ratio was used as an indicator of CYP1A2 activity. The 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine (1X) ratio indicated NAT2 activity. The odds ratio for the slow NAT2 phenotype associated with black race was 0.4; 95% confidence intervals 0.2–0.7. The putative combined low risk phenotype (slow CYP1A2/rapid NAT2) was more common in blacks than in whites (25% vs. 15%, P<0.02). There were no significant racial differences in slow and rapid CYP1A2 phenotypes, and in the combined slow NAT2/rapid CYP1A2 phenotype. Age, education, cigarette smoking amount, body mass index, GSTM1 and GSTM3 genotypes were unrelated to CYP1A2 and NAT2 activity. Intake of cruciferous vegetables (primarily broccoli), red meat, carrots, grapefruit and onions predicted CYP1A2 activity either for all subjects or in race-specific analyses. Carrot and grapefruit consumption was related to NAT2 activity. Collectively, these results indicated that phenotypic differences in NAT2 alone or in combination with CYP1A2 might help explain the higher incidence rates of transitional cell bladder cancer in whites.

Keywords: Abbreviations; CYP1A2; cytochrome P4501A2; NAT2; N; -acetyltransferase-2; 17X; paraxanthine (1,7-dimethylxanthine); 137X; caffeine (trimethylxanthine); 17U; 1,7-dimethyluric acid; 4-ABP; 4-aminobiphenyl; AFMU; 5-acetyl-amino-6-formylamino-3-methyluracil; 1X; 1-methylxanthine; GSTM1; glutathione transferase M1; GSTM3; glutathione transferase M3; HPLC; high performance liquid chromatography; cpd; cigarettes smoked per day; OR; odds ratio; CI; confidence interval; POR; proportional odds ratioBladder; Cancer; Smoking; Acetylation; Cytochrome P450; Caffeine
Featured Book
Web Search
Powered by Plone CMS, the Open Source Content Management System

This site conforms to the following standards: