Biomedical subjects

C R Jones

Publications and source records attributed to C R Jones.

At least 55 records · Page 3Linked to original sources

PubMed1995

Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans.

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42-4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 +/- 9 years, 77 +/- 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P), or 30, 100, and 300 mg, remikiren; panel II, placebo or 300, 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean +/- SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 +/- 74 mmol/24 h; prestudy, 66 +/- 33, 59 +/- 41, 78 +/- 4, 73 +/- 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 +/- 0.3 ng AI/ml/h; before dosing, P, 6.5 +/- 3.1; 30 mg, 8.2 +/- 3; 100 mg, 9.4 +/- 5.7; 300 mg, 6.5 +/- 2.4; 600 mg, 5.2 +/- 2; 1,000 mg, 6.2 +/- 4.4 ng AI/ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Receptor density in the rat heart following ischaemia and prolonged reperfusion.

1. The free radical scavenger MDL 73,404 decreases infarct size and improves heart performance after myocardial ischaemia and prolonged reperfusion. In the present study the possibility that changes in receptor density might contribute to the MDL 73,404-induced increase in contractility has been investigated in rats subjected to myocardial ischaemia and 8 days of reperfusion. 2. Both in saline- and MDL 73,404-treated rats a significant decrease in beta1- and increase in beta2-adrenoceptor densities was apparent in the infarcted tissue. 3. In non-infarcted septum and right ventricle tissue ischaemia followed by reperfusion tended to increase the density of beta2-adrenoceptors which was significantly increased after MDL 73,404 treatment. 4. The increased density of beta2-receptors in the non-infarcted tissue may contribute to the MDL 73,404 induced improvement of cardiac performance.

Animals↗

PubMed1995

Reoperative coronary artery bypass surgery: early and late results and management in 1300 patients.

In this retrospective series overall results after reoperative coronary artery bypass surgery and the subsequent management of recurrent ischemic heart disease in these patients were reviewed. Between September 1980 and September 1993, 17% (n = 1300) of our patients (Pts) undergoing myocardial revascularization (CABG) were reoperative. Of these, 75% were male and 17% were > or = 70 years. One or both internal thoracic arteries (ITA) were used in 25% Pts; a saphenous vein graft (SVG) was used sequentially in 67% or as a separate conduit in 8%. Hospital mortality was higher after redo CABG than after primary CABG (6.9% vs 2.1%, p < 0.0001) and also in Pts receiving SVG rather than IMA as a conduit (7% vs 3.8%, p < 0.001), and in Pts receiving retrograde coronary sinus cardioplegia (RCSC) (n = 504) as compared to those who received antigrade cardioplegia since 1989 (n = 334) (2.5 vs 5.4%, p < 0.05). Throughout the series, independent predictors of hospital mortality by multivariate analysis were: female gender, postoperative myocardial infarction, congestive cardiac failure and stroke. Actuarial survival at 10 years for the patients receiving ITA as a conduit was 86% and for the patients receiving SVG only 76% (p < 0.02); for patients > 70 years was 66% and for patients < 70 years 80% (p < 0.005). Pts with a LVEF < 20% had a poor survival after 2 years. At 10 years cardiac related event free survival after 1st reoperation was 53%. During 13 years 94 Pts underwent subsequent reoperations and 125 Pts underwent saphenous vein graft angioplasty (PTCA), for recurrent ischemic heart disease. Cardiac event free survival at 6 years was clearly superior after multiple reoperative surgery than after graft angioplasty (45% vs 35% p < 0.05). In conclusion, in this series, use of the ITA as a conduit and RCSC has significantly improved Pts survival after redo CABG. Survival and quality of life were further improved in patients requiring multiple reop CABG or graft PTCA.

Age Factors↗

PubMed1994

Subchronic dietary exposure to Aroclor 1254 in rats: accumulation of PCBs in liver, blood, and adipose tissue and its relationship to induction of various hepatic drug-metabolizing enzymes.

Female F344/NCr rats were exposed continuously (7-84 days) or discontinuously (7 days exposure/21 days control diet or 28 days exposure/56 days control diet) to various dietary concentrations (1-100 ppm) of Aroclor 1254. There were dose- and time-dependent increases in PCB levels in liver, blood, and adipose tissue. Following removal of the rats from diet containing Aroclor 1254, there was a relatively rapid decrease in PCB levels, particularly in rats exposed to higher concentrations of Aroclor 1254. In parallel with the alterations in PCB levels observed, the rats showed striking dose- and time-dependent increases in hepatic levels of CYP1A1 and CYP1A2, as determined by various methods [RNA analysis, immunochemical detection, or measurement of the O-dealkylation of methoxyresorufin (CYP1A2) or ethoxyresorufin (CYP1A1)]. In rats removed from the Aroclor 1254 diet, catalytic activity for CYP1A1 as well as RNA levels for both CYP1A1 and CYP1A2 rapidly diminished. In contrast to the high levels of induction of CYP1A1 and CYP1A2 observed, limited induction (< 5-fold) of epoxide hydrolase, quinone oxidoreductase, and aldehyde dehydrogenase was detected, even in rats exposed to the highest concentration of Aroclor (100 ppm) for up to 84 days. Furthermore, induction of these non-CYP hepatic drug-metabolizing genes exhibited distinctly different concentration-response curves. The ratios of hepatic CYP1A1 activity to hepatic PCB burden were similar for rats exposed continuously to Aroclor in the diet for 7, 28, or 84 days, and for rats exposed discontinuously (7 days Aroclor/21 days control diet or 28 days Aroclor/56 days control diet). Thus, hepatic PCB levels alone appeared to be reasonably predictive of CYP1A1 levels under a variety of modes of exposure. When the ratio of CYP1A1 activity to adipose or blood PCB concentration was determined, similar ratios were observed for rats exposed continuously for 7, 28, or 84 days. However, lower ratios were observed for rats discontinuously exposed to Aroclor in the diet. These results have important implications with respect to: (a) employing PCB levels in various tissues to predict biological effects, and (b) determining different concentration-response curves for the various biological effects induced by PCBs.

Adipose Tissue↗

PubMed1994

Angioplasty versus coronary artery bypass in octogenarians.

We retrospectively analyzed early and late results for two treatment strategies of significant coronary artery disease in 310 octogenarians seen in the last 10 years. One hundred five patients 80 or more years of age had percutaneous transluminal coronary angioplasty (PTCA) and 205 had coronary artery bypass grafting (CABG). The PTCA group differed from the CABG group in having a greater proportion of women (71.4% versus 45.8%; p < 0.001); fewer patients with unstable angina (24.7% versus 33.6%; p < 0.04), acute myocardial infarction (11% versus 23%; p < 0.04), three-vessel coronary artery disease (20% versus 56%; p < 0.0001), and a left ventricular ejection fraction less than or equal to 0.30 (10% versus 21%; p < 0.008); and fewer vessels revascularized (1.2 +/- 0.6 versus 3.5 +/- 0.9; p < 0.0001). Hospital mortality was 8.57% after PTCA (9/14 failed PTCA) and 5.8% after CABG (4/14 emergent, 6/101 urgent, and 2/90 elective). Hospital stay was 7 +/- 0.9 days after PTCA and 14 +/- 1.5 days after CABG (p < 0.01). Independent predictors of hospital mortality obtained by multivariate analysis included failed PTCA and acute myocardial infarction (PTCA group), a left ventricular ejection fraction equal to or less than 0.30, and acute myocardial infarction and emergency CABG (CABG group). Survivors after both CABG and PTCA showed a significant improvement in their New York Heart Association class. Actuarial survival at 5 years after PTCA was 55% and after CABG it was 66% (p < 0.01). Cardiac event-free survival (deaths, myocardial infarction, PTCA, CABG) at 3 years was 61% after PTCA and 81% after CABG (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1994

Surgical management in patients with coexistent coronary and cerebrovascular disease. Long-term results.

Between January 1980 and December 1992, 3% (210/6,862) of our patients undergoing myocardial revascularization (CABG) had high grade (> 80%) internal carotid stenosis (CS). One hundred seventy-five of these patients with complete follow up for a minimum of 18 months were studied. Bilateral internal CS was present in 60%, and 75% had other vascular lesions, mainly as peripheral vascular disease (PVD) of the lower limb (50.8%). All patients underwent CAE (carotid endarterectomy) followed by CABG under the same anesthesia. Peripheral vascular lesions, contralateral internal CS and recurrent (n = 43) and progressive vascular lesions (n = 50), were subsequently treated as staged procedures. Hospital mortality was 3.42%. By univariate analysis significant predictors of late mortality were congestive heart failure, COPD, PVD, postoperative myocardial infarction, postoperative stroke, and ischemic cardiomyopathy. Only the latter two were also significant by multivariate analysis. At 12 years, actuarial survival in the presence of these risk factors were 46%, 49%, 22%, 37%, 53%, and 27% respectively. All are significantly lower as compared with the corresponding subsets of patients with the risk factor absent. At 12 years, actuarial survival for the entire series was 65%. Cumulative incidence of postoperative strokes was higher in patients with bilateral internal CS than in patients with unilateral internal CS (p < 0.07) and in patients with neurologic symptoms than asymptomatic patients. At 12 years, actuarial freedom from all cardiac related events, postoperative stroke, and symptomatic PVD were 49%, 82%, and 76% respectively. After successful revascularization these patients should be carefully followed for recurrent and progressive vascular lesions.

Adult↗

PubMed1993

Modelling and modification of the binding site of endothelin and other receptors.

From three-dimensional models of its receptors, residues which bind the carboxy-terminus of endothelin were predicted. This site is in a pocket consisting of five putative transmembrane helices and includes a histidine in the sixth helix. This residue is either phenylalanine or asparagine in cationic neurotransmitter receptors. The histidine alkylating agent diethylpyrocarbonate potently inhibited binding of [125I]endothelin-1 to its receptors in bovine cerebellum, where a single population of endothelin ETB receptors was shown to exist. From the absence of pH sensitivity of inhibition above pH 5 and the reversal by hydroxylamine of inhibition, diethylpyrocarbonate is concluded to inhibit by histidine modification. Diethylpyrocarbonate inhibited ligand binding to several receptors with the potency order endothelin ETB > or = bombesin > or = dopamine D2 > or = m2 muscarinic > alpha 1-adrenoceptor > or = m 1 muscarinic > 5-HT2. This is consistent with histidine in the binding site of endothelin (and some other peptidergic) receptors and the proposed model.

Amino Acid Sequence↗

PubMed1993

Comparative pharmacodynamics of CYP2B induction by phenobarbital in the male and female F344/NCr rat.

The phenobarbital dose-CYP2B induction response relationships and pharmacodynamics of CYP2B induction have been characterized in female and male F344/NCr rats. The ED50 and EC50 values for the induction, by phenobarbital, of hepatic CYP2B1 or 2B1/2B2 protein or associated catalytic activities (benzyloxy- or pentoxyresorufin O-dealkylation or testosterone 16 beta-hydroxylation) were 2- to 7-fold higher in the female than in the male rat, indicating a somewhat decreased potency for this effect in the female rat. In contrast, the maximal induction, expressed as the ratio of induced activity to control activity, was as great or greater in the female rat than in the male. Thus, any difference in the responsiveness of female rats to hepatic CYP2B induction by phenobarbital, compared to male rats, is reflected in potency but not degree of induction of catalytic activity or immunoreactive protein.

Animals↗

PubMed1993

Inhibition of cytochromes P450 by nitric oxide and a nitric oxide-releasing agent.

The effect of nitric oxide (NO) on cytochrome P450-mediated benzyloxyresorufin and ethoxyresorufin O-dealkylase activity of rat hepatic postmitochondrial (S-9) or microsomal subfractions, or purified rat liver CYP2B1, was examined. Two distinct inhibitory phases were observed regardless of whether the NO was added prior to initiation of the reactions with NADPH or during the course of substrate turnover. The first was a reversible inhibition characterized by complete cessation of catalytic activity, the duration of which was NO concentration-dependent with an IC50 in the range of 8-60 microM. This phase was followed by a second, irreversible, inhibitory phase characterized by a varying extent of recovery of activity, with inhibition ranging from < 1 to approximately 100%. The extent of this diminution in substrate conversion rate was also NO concentration-dependent, with an IC50 in the range of 13-72 microM, and could be partially abrogated by the inclusion of bovine serum albumin in the reaction mixture. Lower IC50 values for both inhibitory phases were obtained in the case of benzyloxyresorufin O-dealkylase activity than in the case of ethoxyresorufin O-dealkylase activity, suggesting a differential susceptibility to inhibition by NO for the two O-dealkylase activities. A nitric oxide-releasing compound ([Et2NN(O)NO]Na,DEA/NO) caused qualitatively similar inhibitory effects on benzyloxyresorufin O-dealkylase activity when added prior to the initiation of the reactions with NADPH, or during the course of substrate turnover. Based upon these results, it is possible that NO may play a role in the regulation of P450 activity in vivo.

Animals↗

PubMed1993

The STA2 and MEL1 genes of Saccharomyces cerevisiae are idiomorphic.

The STA2 (glucoamylase) gene of Saccharomyces cerevisiae has been mapped close to the end of the left arm of chromosome II. Meiotic analysis of a cross between a haploid strain containing STA2, and another strain carrying the melibiase gene MEL1 (which is known to be at the end of the left arm of chromosome II) produced parental ditype tetrads only. Since there is no significant DNA sequence similarity between the STA2 and MEL1 genes, or their respective flanking regions, we conclude that these two genes are carried by separate non-hybridizing sequences of chromosomal DNA, either of which can reside at the end of the left arm of chromosome II. By analogy with the mating-type locus of Neurospora crassa, we suggest that the STA2 and MEL1 genes are idiomorphs with respect to one another.

Base Sequence↗

PubMed1993

Skin graft storage and keratinocyte viability.

The viability of human split skin grafts stored in four solutions has been assessed by monitoring the percentage of viable keratinocytes in the stored grafts. Skin grafts stored in RM+ (Ready Mix) tissue culture medium remained more viable than those stored in Hartmann's, Marshall's or saline solutions. By day 10 (postoperative), the percentage of viable keratinocytes of those grafts stored in RM+ was around 85%, compared to a value of around 10% for the other media. By day 30, RM+ achieved a value of around 60% keratinocyte viability compared to a value approaching 1% in the other storage media under investigation. RM+ provides mitogens, nutrients, growth factors and physiological pH, all of which are important factors for successful skin graft storage.

Adolescent↗

PubMed1993

A porcine model using skin graft chambers for studies on cultured keratinocytes.

In wound healing research, animal models permit an extensive tissue analysis which is not normally possible in clinical studies. A morphological comparison of human and porcine skin was made in order to identify those aspects of the wound healing process where a porcine model may help our understanding of clinical problems. We describe a porcine model for evaluating the growth of cultured keratinocytes on a variety of wound beds. Polytetrafluoroethylene skin graft chambers were used to isolate wounds and prevent epidermal healing from the skin edge. The chambers remained in situ for 5-7 weeks. We detail the surgical technique, the method of porcine keratinocyte culture and highlight some practical measures that were taken to optimise the "take" of the cultured keratinocyte grafts.

Animals↗

PubMed1993

Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzne (TCPOBOP) in rat and cultured rat hepatocytes.

1. The dose-response relationships for hepatic CYP2B induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were examined in the male F344/NCr rat. TCPOBOP, administered for 14 days at 0-1000 ppm in the diet, caused concentration-dependent induction of hepatic CYP2B1 protein and RNA, and of CYP2B-mediated catalytic activities (benzyloxy- and pentoxyresorufin O-dealkylation, and testosterone 16 beta-hydroxylation). ED50 values for CYP2B induction were > or = 300 ppm dietary TCPOBOP. The maximal inductions observed were 66-88% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 2. The EC50 values for hepatic CYP2B induction were 1.5-3.0 microM (based on serum TCPOBOP) and 15-20 mumol/kg liver. 3. The maximal inductions of isozymes of the CYP3A subfamily, of microsomal epoxide hydrolase, and of glutathione S-transferases Ya/Yc and Yb1/Yb2 in rats exposed to TCPOBOP were 58-74% of those resulting from exposure of the rats to 500 ppm dietary phenobarbital. 4. The ED50 value for induction of benzyloxyresorufin O-dealkylation in cultured rat hepatocytes by TCPOBOP was determined to be 0.93 microM. The maximal induction of this activity caused by TCPOBOP was 87% of the maximum increases caused by phenobarbital. 5. The results indicate that TCPOBOP is a highly effective phenobarbital-type inducer in the rat when administered in the diet for 2 weeks at 1000 ppm. When extent of induction is related to serum total xenobiotic level, TCPOBOP would appear to be at least as potent as, if not more potent than, phenobarbital in the rat.

Animals↗

PubMed1992

Induction of a pleiotropic response by phenobarbital and related compounds. Response in various inbred strains of rats, response in various species and the induction of aldehyde dehydrogenase in Copenhagen rats.

The ability of phenobarbital (PB) to induce a "pleiotropic response" which includes both cytochromes P450 (CYP) as well as other drug-metabolizing enzymes was investigated in mice, rabbits, hamsters, and various inbred strains of rats. PB induced similar drug-metabolizing enzymes (CYP2B, CYP3A, and epoxide hydrolase) in rats, mice, rabbits and hamsters. PB and two structural analogues (ethylphenylhydantoin and barbital) induced a variety of drug-metabolizing enzymes (CYP2B, CYP3A, CYP2A, epoxide hydrolase) in a series of inbred strains of rats. In contrast, levels of aldehyde dehydrogenase (ALDH) (propionaldehyde, NAD+) which were expressed constitutively in all strains of rats were induced by PB in only two of the eight strains (ACI, Copenhagen). Further investigations of ALDH induction by structurally diverse compounds in Copenhagen rats demonstrated a strong correlation between the induction of ALDH and other elements of the pleiotropic response (CYP2B, CYP3A, epoxide hydrolase). These results imply that induction of ALDH (propionaldehyde, NAD+) is associated with the PB pleiotropic response in Copenhagen rats.

Aldehyde Dehydrogenase↗

PubMed1992

A pleiotropic response to phenobarbital-type enzyme inducers in the F344/NCr rat. Effects of chemicals of varied structure.

The effects of a number of phenobarbital-type inducers on selected drug-metabolizing enzymes in male F344/NCr rats were determined by measuring specific catalytic activities and/or by measuring the levels of RNA which hybridize with specific probes for the corresponding genes. The effects on hepatic CYP2B1 were assessed by measuring the levels of CYP2B1-specific RNA and benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Levels of CYP3A were monitored by measuring the rate of hydroxylation of testosterone at the 6 beta-position. Microsomal epoxide hydrolase activity was determined by measurement of cellular RNA specific for this form and by assaying the hydrolysis of benzo[a]pyrene-4,5-oxide. UDP-glucuronyltransferase activity was assayed by measuring the glucuronidation of 3-hydroxybenz[a]anthracene. Levels of glutathione S-transferase Ya/Yc were measured by quantifying total cellular RNA coding for the proteins. When male F344/NCr rats were administered various doses of phenobarbital or dichlorodiphenyltrichloroethane (DDT), strong correlations between the induction of CYP2B1 and the induction of epoxide hydrolase or UDP-glucuronyltransferase activities were observed. Treatment of rats with barbiturates, hydantoins, halogenated pesticides such as DDT or alpha-hexachlorocyclohexane, 2,4,5,2',4',5'-hexachlorobiphenyl, CYP2B1 inhibitors such as clotrimazole or clonazepam, or such structurally-diverse compounds as 2-hexanone or diallyl sulfide resulted in induction of CYP2B1-mediated enzyme activity and induction of certain other forms of cytochrome P450, microsomal epoxide hydrolase, at least one form of UDP-glucuronyltransferase, and multiple forms of glutathione S-transferase. This suggests that, as a class, compounds which induce CYP2B1 also induce a coordinate hepatic pleiotropic response which includes induction of these other phase I and phase II drug-metabolizing enzymes.

Animals↗

PubMed1992

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.

Animals↗

PubMed1992

Brain dopamine D-2 receptor mechanisms in spontaneously hypertensive rats.

Brain dopaminergic function was studied in spontaneously hypertensive rats (SHR) with the selective dopamine D-2 antagonist sulpiride. Sulpiride dose-dependently inhibited locomotor activity of normotensive Wistar-Kyoto rats (WKY). SHR showed an increase in locomotor activity in response to low doses of sulpiride, whereas no effect was observed of higher doses. In a two-bottle salt-preference test, WKY showed increased preference for an 0.9% saline solution after treatment with sulpiride, whereas total fluid intake remained the same. In SHR, sulpiride influenced neither salt-preference nor total fluid intake. SHR and WKY with a unilateral lesion of the median forebrain bundle showed similar turning behaviour in response to treatment with amphetamine. Pretreatment with 100 mg/kg sulpiride virtually abolished amphetamine-induced turning in WKY, but had little effect in SHR. Sulpiride dose-dependently increased serum prolactin concentrations in WKY and SHR. However, the increase was significantly greater in SHR. Dopamine D-2 receptor binding was measured with in vitro autoradiography, using [125I]-sulpiride as the ligand. Binding density was similar in the caudate nucleus and substantia nigra of SHR and WKY brain. Concentrations of the dopamine metabolites DOPAC and HVA, but not of dopamine itself, were significantly increased in frontal cortex, striatum and hypothalamus after treatment with 100 mg/kg sulpiride. There were no significant differences between SHR and WKY in the increase in the DOPAC/DA and HVA/DA ratio. These data show that SHR show differential changes in their response to central dopamine D-2 blockade when compared to WKY. Thus, in some tests (locomotor activity after high doses, salt preference, turning behaviour), SHR respond less to sulpiride.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Induction of hepatic CYP1A in male F344/NCr rats by dietary exposure to Aroclor 1254: examination of immunochemical, RNA, catalytic, and pharmacokinetic endpoints.

Male F344/NCr rats were exposed to low dietary concentrations of Aroclor 1254 (0-33 ppm) for 7 days, following which the induction of selected hepatic drug metabolizing enzymes was monitored. CYP1A1, measured indirectly by assaying the O-dealkylation of ethoxyresorufin in 9000 g supernatants, was increased 1.5-, 3-, 8-, and 37-fold following 7 days of exposure to 1.0, 3.3, 10, and 33 ppm Aroclor, respectively. In contrast, the O-dealkylation of benzyloxyresorufin, an indirect measure of CYP2B1 activity, was increased approximately 4-fold following exposure to 33 ppm dietary Aroclor. Measurement of the non-P450-mediated activities epoxide hydrolase, DT-diaphorase, and aldehyde dehydrogenase (NADP+, benzaldehyde) revealed < 4-fold inductions following feeding of 33 ppm Aroclor. In view of the relatively high sensitivity of the CYP1A-specific catalytic endpoint as a biomarker for Aroclor exposure, alternative endpoints for detecting induction of this subfamily of P450 were also examined. The extent of in vivo CYP1A induction was assessed by measuring serum concentrations of zoxazolamine 150 min following an intraperitoneal dose of 100 mg/kg body wt. Slight decreases in serum zoxazolamine concentration were observed in rats exposed to as little as 1.0 ppm dietary Aroclor 1254, while profound decreases were seen in rats exposed to > or = to 10 ppm Aroclor. Immunodetection of CYP1A1 protein, with a monoclonal antibody directed against this cytochrome, revealed a 2.9-fold increase in rats exposed to as little as 1.0 ppm Aroclor, and approximately 10- and 44-fold increases following exposure to 3.3 and 10 ppm dietary Aroclor, respectively. Increases in total hepatocellular RNA coding for CYP1A1 and CYP1A2, quantified by hybridization to specific oligonucleotide probes, corresponded well to the increases in hepatic O-dealkylase activity for ethoxyresorufin (CYP1A1) and methoxyresorufin (CYP1A2), respectively. Thus, CYP1A induction, directly or indirectly measured with a variety of endpoints, represents a highly sensitive biomarker for exposure to relatively low doses of Aroclor 1254 in the rat.

Administration, Oral↗