Effect of adrenalectomy,pretreatment with SKF 525-A,phenobarbital and diethyl maleate on the acute toxicity of fenitrothion in male rats

The effect of adrenalectomy (Adx), SKF 525-A, phenobarbital (PB), and diethyl maleate (DEM) on the acute toxicity of fenitrothion was investigated in male rats by assessing the degree of plasma cholinesterase activity. PB, 60 mg/kg/day for 3 days, exerted no protective effect on the toxicity of fenitrothion (100 mg/kg, p.o.) given 24 h after the last injection. In adrenalectomized and SKF 525-A-pretreated rats, the toxicity of fenitrothion was lower than that of the controls. Fenitrothion toxicity was increased by administration of DEM (1 ml/kg), which depletes hepatic glutathione (GSH) levels. In vitro, the rates of fenitrothion decomposition and fenitrooxon formation by microsomes were markedly affected by PB, SKF 525-A and Adx. The decomposition of fenitrooxon by the microsomal fraction and GSH-dependent decomposition of fenitrooxon by the soluble fraction were not affected by PB, SKF 525-A and Adx pretreatment. The GSH-dependent decomposition of fenitrothion and fenitrooxon was increased by addition of GSH to the incubation mixture. The present results indicate that the GSH-dependent metabolic pathway plays an important role in the detoxication of fenitrothion.     

Tissue distribution of inducible aldehyde dehydrogenase activity in the rat after treatment with phenobarbital or methylcholanthrene

Two genetically distinct substrains of the Wistar rat (RR and rr) were used to study the tissue distribution of the inducibility of aldehyde dehydrogenase (ALDH). The RR substrain is responsive to phenobarbital (PB), as far as the induction of the hepatic ALDH activity is concerned, whereas the rr substrain is deprived of this biochemical property. Both substrains, however, respond to treatment with methylcholanthrene (MC), exhibiting a uniform increase of the ALDH activity in the liver. It is known that PB and MC induce two different isozymes of the hepatic cytosol. The effect of PB (1 g/l in drinking water, for 12 days) on the inducibility of ALDH in extrahepatic tissues was examined in the RR substrain. On the contrary, MC was given (50 mg/kg x 4, intraperitoneally) to rr animals. The activity of ALDH was found to be induced by PB in the liver and the intestinal mucosa, when measured with NAD and propionaldehyde (P/NAD) or phenylacetaldehyde (Ph/NAD). An increase of the activity was also noticed when ALDH was measured with NADP and benzaldehyde (B/NADP). In rr animals, MC induced the B/NADP activity in the liver, the intestinal mucosa, the kidneys, the lungs, the spleen, the brain, the urinary bladder and the heart. The effect of MC on various tissues was less distinct, when ALDH was measured as P/NAD or Ph/NAD activity. It is concluded, that PB and MC not only induce different types of ALDH activity, but they also reveal differences in the tissue distribution of the inducibility of ALDH.     

Involvement of phenobarbital and SKF 525A in the hepatotoxicity of antifungal drugs itraconazole and fluconazole in rats

Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), gamma-glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and gamma-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.     

Effect of 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A) on sulphacetamide distribution and excretion in rats

1. Administration of 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A), 40 mg/kg, i.p., simultaneously or 40 min before sulphacetamide sodium, 100 mg/kg, i.p., was associated with a three-fold increase in sulphacetamide plasma concentration of rats. This effect was no longer evident after 30 minutes.2. The augmentation in sulphacetamide plasma concentration was associated with parallel increases in the muscle, kidney and brain tissue. The stomach was the only organ that contained less sulphacetamide.3. When sulphacetamide was administered i.v., a similar phenomenon was observed but the differences were less marked.4. Pretreatment with SKF 525-A was associated with decreased excretion of sulphacetamide by the kidney.5. It is concluded that SKF 525-A may alter the distribution and excretion of drugs as well as inhibiting drug metabolizing enzymes.     

Involvement of Phenobarbital and SKF 525A in the Hepatotoxicity of Antifungal Drugs Itraconazole and Fluconazole in Rats

Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), γ-glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and γ-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.     

Relation between hepatic microsomal metabolism of N-nitrosamines and cytochrome P-450 species

Effects of SKF 525A (0.1 mM), metyrapone (0.1 mM), alpha-naphthoflavone (ANF) (0.5 mM) and pyrazole (1.0 mM) on N-nitrosodimethylamine (NDMA), N-nitrosomethylbutylamine (NMBuA) and N-nitrosomethylbenzylamine (NMBeA) metabolism by hepatic microsomes from rats pretreated with inducers were investigated. NDMA demethylation was weakly increased by phenobarbital (PB) treatment. The demethylation was inhibited by SKF 525A and enhanced by metyrapone in non-treated and PB-treated microsomes, and weakly inhibited by ANF in 3-methylcholanthrene(MC)-treated microsomes. NMBuA demethylation was increased by PB treatment and inhibited by SKF 525A in all microsomes. Metyrapone inhibited the demethylation in PB-treated microsomes. NMBuA debutylation was increased by PB and MC treatments, and inhibited by metyrapone in all microsomes. The strongest inhibition by metyrapone was observed in PB-treated microsomes. The debutylation was inhibited by SKF 525A in non-treated and PB-treated microsomes and by ANF in MC-treated microsomes. NMBeA demethylation was decreased by MC treatment and weakly inhibited by SKF 525A in all microsomes. The effects of the inducers and inhibitors on NMBeA debenzylation were almost the same as those on NMBuA debutylation except that the increasing effect of MC was small. Pyrazole was a relatively selective inhibitor of NDMA demethylation. These results suggest the following: NDMA demethylation is catalyzed by PB-induced cytochrome P-450 species (P450-PB) and MC-induced cytochrome P-450 species (P448-MC). But their specific activity is low and the other cytochrome P-450 species demethylate NDMA. NMBuA demethylation is catalyzed by P450-PB. But the specific activity is not high and the other cytochrome P-450 species also demethylate NMBuA. NMBuA debutylation is catalyzed by P450-PB and P448-MC. Almost all of NMBeA demethylation is catalyzed by cytochrome P-450 species other than P450-PB and P448-MC. NMBeA debenzylation is catalyzed by P450-PB and P448-MC, but the specific activity of P448-MC is not high.     

Responsiveness of cerebral and hepatic cytochrome P450s in rat offspring prenatally exposed to lindane

Prenatal exposure to low doses of lindane has been shown to affect the ontogeny of xenobiotic metabolizing cytochrome P450s (CYPs), involved in the metabolism and neurobehavioral toxicity of lindane. Attempts were made in the present study to investigate the responsiveness of CYPs in offspring prenatally exposed to lindane (0.25 mg/kg b. wt.; 1/350th of LD(50); p. o. to mother) when challenged with 3-methylcholanthrene (MC) or phenobarbital (PB), inducers of CYP1A and 2B families or a sub-convulsant dose of lindane (30 mg/kg b. wt., p. o.) later in life. Prenatal exposure to lindane was found to produce an increase in the mRNA and protein expression of CYP1A1, 1A2, 2B1, 2B2 isoforms in brain and liver of the offspring at postnatal day 50. The increased expression of the CYPs in the offspring suggests the sensitivity of the CYPs during postnatal development, possibly, to low levels of lindane, which may partition into mother's milk. A higher increase in expression of CYP1A and 2B isoenzymes and their catalytic activity was observed in animals pretreated prenatally with lindane and challenged with MC (30 mg/kg, i. p. x 5 days) or PB (80 mg/kg, i. p. x 5 days) when young at age (approx. 7 weeks) compared to animals exposed to MC or PB alone. Further, challenge of the control and prenatally exposed offspring with a single sub-convulsant dose of lindane resulted in an earlier onset and increased incidence of convulsions in the offspring prenatally exposed to lindane have demonstrated sensitivity of the CYPs in the prenatally exposed offspring. Our data assume significance as the subtle changes in the expression profiles of hepatic and cerebral CYPs in rat offspring during postnatal development could modify the adult response to a later exposure to xenobiotics.     

The influence of metabolism on the MAO-B inhibitory potency of selegiline

(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.25-0.5 mg/kg) of (-)-deprenyl in rat brain and liver were compared, using either oral or subcutaneous drug administration. The intensity of the first pass metabolism of (-)-deprenyl was also estimated. The effect of pre-treatment with phenobarbitone (80 mg/kg i.p., daily for three days) or proadifen (SKF-525A, 50 mg/kg i.p., single dose) on the MAO-B inhibitory potency of (-)-deprenyl was also studied. The oral and subcutaneous administration of selegiline induced a significantly different degree of MAO-B enzyme inhibition in the rat brain, but not in the liver. The inhibitory potency of (-)-deprenyl on MAO-B activity was markedly influenced by pre-treatment of rats with an inducer (phenobarbitone), or an inhibitor (SKF-525A) of cytochrome P-450 mono-oxygenases in the liver. Our results suggest, that (-)-deprenyl is metabolised mainly in the liver by microsomal cytochrome P-450 dependent mono-oxygenases, and it has an intensive first-pass metabolism. The parent compound is responsible for the inhibition of MAO-B enzyme activity.     

Drug-induced porphyrin biosynthesis—XI. effect of SKF 525-A on the activity of porphyrin-inducing drugs in chick embryos,chickens and rats

Hexobarbital (100 mg/kg) induces a marked elevation of hepatic δ-aminolevulinic (ALA)-synthetase and porphyrin levels in the 17-day-old chick embryo but is inactive in the 18-day-old chicken. Propylisopropylacetamide (PIA, 100 mg/kg) induces a marked elevation of ALA-synthetase activity in the 17-day-old chick embryo but only a small elevation in the 18-day-old chicken. After pretreatment of 18-day-old chickens with 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A), hexobarbital and PIA (100 mg/kg) induce a marked elevation of hepatic ALA-synthetase and porphyrin levels. The hepatic level of uncharged PIA was significantly higher in SKF 525-A-pretreated than in untreated chickens. Chick embryo liver is more sensitive to porphyrin-inducing drugs than chicken liver. However, after blockade of drug metabolism by SKF 525-A, the lower sensitivity of the chicken liver is compensated for by high levels of uncharged drug. After pretreatment of the 17-day-old chick embryo with SKF 525-A, the porphyrin-inducing activity of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) and of PIA is increased while that of allylisopropylacetamide (AIA) and 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine (Ox-DDC) is not affected. PIA (300 mg/kg) which did not produce an increase in hepatic ALA-synthetase activity in rats elicits a slight but significant increase in the SKF 525-A-pretreated rat.     

Acute sedative properties of SKF 525 A in rats: Implications for its use as a metabolism inhibitor in the study of psychoactive drugs

SKF 525 A was found possess sedative properties in rats at doses of 25 and 50 mg per kg, when injected intraperitoneally. The behavioural effects of the drug were assessed in two ways. Firstly, by Time Sampling Behavioural Categorisation of exploratory behaviour; and secondly by activity measurements obtained with an ultrasonic motion recorder. The results clearly demonstrate that SKF 525A has sedative properties in rats at doses which are conventionally used to inhibit metabolism of a wide range of drugs. The implications of these results for the use of SKF 525 A in the study of the actions of psychotropic drugs are discussed.     

Changes in pentobarbital hypnosis and hepatic metabolism in streptozotocin-diabetic mice

The present study deals with the hypnotic effect of pentobarbital (Pento) in relation to its metabolism in hepatic microsomes in streptozotocin (STZ, 170 mg/kg, i.p.) injected mice. Liver weight (mg/10 g body wt.) of STZ-treated mice was larger than that of the controls throughout the experimental period. Although the shortening of sleeping time induced by Pento (60 mg/kg, i.p.) was always observed, Pento-metabolizing enzyme activity (by the method of Kato et al., 1964) increased in mice with diabetes for 2 and 4 weeks but decreased in mice with diabetes for 8 weeks. Induction following phenobarbital (100 mg/kg, s.c.) and inhibition by SKF 525-A (10 mg/kg, i.p.) of hepatic metabolizing enzyme were found in both control and mice with diabetes for 2, 4 and 8 weeks, but these were not definitely correlated to their hepatic Pento-metabolizing enzyme activities. STZ-induced hyperglycemia and shortening of sleeping time by Pento were completely prevented by the pretreatment with nicotinamide (500 mg/kg, i.p.). NPH-insulin injection partially decreased hyperglycemia in STZ-diabetic mice, but sleeping time by Pento was not significantly affected. These results suggest that the hyposensitivity to Pento in STZ-diabetic mice is partially related to an abnormality of metabolism in liver such as the hyperglycemic state.     

Possible mechanism of adverse reaction following levodopa plus benserazide treatment.

1 Rats treated for seven days with seryl-trihydroxybenzylhydrazine (benserazide), and inhibitor of peripheral aromatic L-amino acid decarboxylase (500 mg/kg, daily, i.p.) alone or in combination with L-DOPA methylester (500 mg/kg, daily, i.p.) for seven days showed a moderate but significant decrease of liver aldehyde dehydrogenase (ALDH), without accompanying change in alcohol dehydrogenase (ADH) activity, compared with saline-treated controls. 2 Administration of L-DOPA methylester (500 mg/kg, daily, i.p.) alone for seven days had little effect on liver ADH or ALDH. 3. The combined treatment might be conducive to the in vivo formation of L-DOPA-derived tetrahydroisoquinoline derivatives which might be implicated in L-DOPA produced adverse effects.     

Cocaethylene hepatotoxicity in mice.

Cocaethylene is a novel metabolite of cocaine formed in the presence of ethanol. When administered to ICR male mice in dosages ranging from 10 to 50 mg/kg, i.p., cocaethylene was found to produce dose-dependent hepatic necrosis in the midlobular zone (zone 2). Severity of the lesion was maximal 12-24 hr after administration. A transient but significant decrease in hepatic glutathione content was observed 1 hr after cocaethylene administration. Pretreatment with the cytochrome P450 inhibitors cimetidine (200 mg/kg, i.p., in divided doses) or SKF 525A (50 mg/kg, i.p.) diminished toxicity. Pretreatment of mice with the esterase inhibitor diazinon (10 mg/kg, i.p.) increased cocaethylene hepatotoxicity, as did pretreatment with the cytochrome P450 inducing agents phenobarbital (80 mg/kg/day, i.p., for 3 days) or beta-naphthoflavone (40 mg/kg/day, i.p., for 3 days). Phenobarbital pretreatment also caused a shift in the morphologic site of necrosis from midzonal to peripheral lobular (zone 1) regions. The type of hepatic lesion produced by cocaethylene, its morphologic distribution (including the shift with phenobarbital treatment), the potency of cocaethylene in producing this effect, and the apparent requirement of oxidative metabolism for hepatoxicity were all remarkably similar to observations with its parent compound, cocaine, in this and earlier studies. This suggests that these compounds produce liver toxicity through the same or similar mechanisms.     

Parathion toxicity in relation to liver microsomal oxidases, lipid composition and fluidity

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC), 80 and 20 mg/kg, respectively, for 3 consecutive days and then administered threshold lethal dose of the organophosphorus insecticide, parathion, 10 mg/kg i.p. to compare its toxicity in these, with those fed high fat, diet (HFD-50% saturated fat, and normal diet (ND-10% saturated fat) for 30 days. Hepatic microsomes of these four groups of rats without the parathion administration were also analysed to evaluate toxicity and metabolism of the insecticide in relation to some physico-chemical changes in microsomal membranes. Results showed that in comparison to ND, all three pretreatments (PB, MC and HFD) significantly decreased parathion toxicity, increased microsomal oxidase activity and elevated microsomal cholesterol/phospholipid ratio. However, microsomal cytochrome P-450 was significantly raised only in PB and MC, and microsomal fluidity was significantly raised only in MC, as measured by DPH-fluorescence polarization technique.     

Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse

1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N -acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior toa6-h exposure toeither 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fatof SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting thatmetabolism was decreased; the SO styrene ratio in the fatofPB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.     

Metabolism of metronidazole and antipyrine in isolated rat hepatocytes. Influence of sex and enzyme induction and inhibition

The metabolism of metronidazole and antipyrine was investigated in freshly isolated hepatocytes from 7 male and 6 female control Wistar rats, 8 males and 5 females pretreated with phenobarbital (PB) and 3 males pretreated with 3-methylcholanthrene (MC). Pretreatment with PB increased the intrinsic clearance (CLi = Vmax/Km) of metronidazole to its acetic acid (MAA) and hydroxy metabolite (HM) 7- and 2.8-fold in the males and 3.2- and 3.0-fold in the females, whereas MC treatment increased the values 9- and 10-fold, respectively (P less than 0.05). The CLi of metronidazole to HM and its glucuronide conjugate was higher in the control and PB treated male than in the corresponding female groups, whereas the rank order was reversed for sulphate formation (P less than 0.05). SKF 525A was a more potent inhibitor of MAA formation than of HM formation, except in the PB treated male group. Pretreatment with MC increased the inhibitory potency of alpha-naphthoflavone and antipyrine toward MAA and HM formation. In male rats PB treatment increased the CLi of antipyrine to 3-hydroxymethyl-(HMAP), nor-(NORAP) and 4-hydroxyantipyrine (OHAP) 2.5-, 2.1- and 4.5-fold, respectively (P less than 0.05). Pretreatment with MC in male and with PB in female rats had no significant effect on antipyrine metabolism. SKF 525A was a more potent inhibitor of HMAP and OHAP formation than of NORAP formation. Treatment with MC increased the inhibitory potency of alpha-naphthoflavone toward the formation of all antipyrine metabolites. Metronidazole increased the formation rate of HMAP, but inhibited the formation of NORAP and OHAP, particularly the latter. The results suggest that the formation of MAA, HM, HMAP, NORAP and OHAP from metronidazole and antipyrine is catalyzed by different cytochrome P-450 isozymes, which may be supplemented or substituted by PB or MC induced species. The involved P-450 isozymes have more or less overlapping substrate and product specificity. Metronidazole appears to be a sensitive probe for detection and identification of PB and MC type induction.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

Time course of the induction of aryl hydrocarbon hydroxylase in rat liver nuclei and microsomes by phenobarbital, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin,dieldrin and other inducers

Aryl hydrocarbon hydroxylase (AHH) has been measured in male rat liver nuclei and microsomes after treatment of adult animals with various inducers for up to 14 days. After daily i.p. injections of 3-methylcholanthrene (MC, 20 mg/kg) the nuclear activity increased to a maximum of 600 per cent of the control activity after 4 days whereas the microsomal activity was 400 per cent of control at the same date. After 12 days, both activities equilibrated at 400 per cent. A similar time course was found after a single i.p. injection of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, 0.01 mg/kg) with an induction to 500 and 300 per cent for nuclei and microsomes, respectively, after 2 days, and to 400 per cent for both after 12 days. Phenobarbital (PB) was given continuously in the drinking water (1 g/l) and induced the microsomal activity to 200 per cent after 8 days and 170 per cent after 14 days. the nuclear activity was only slightly induced to a Constant level of 130 per cent between day 8 and 14. Dieldrin did not significantly increase the microsomal activity after daily i.p. injections (20 mg/kg), but the nuclear activity raised to 200 per cent after 3 days and levelled down to control values after 12 days. Other inducers tested were benz[a]anthracene (BA), hexachlorobenzene (HCB) and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). The induction pattern with BA was similar to that of MC, a model compound for the group of cytochrome P448 inducers. the induction by HCB and DDT resembled that by PB, a typical cytochrome P450 inducer.     

Metabolite involvement in the behavioral effects of bromocriptine in cats

There is a lag phase of 30-60 min before the onset of bromocriptine (BC) action. This delay may be necessary for the formation of active metabolites. The objective was to determine whether the abnormal behavioral effects induced by BC involve active hepatic metabolites. Thus, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BC-treated cats. Experiments began after six weeks of habituation and involved i.p. injections of: (1) propylene glycol (drug vehicle); (2) SKF 525A (70 mg/kg); (3) BC (10 mg/kg); and (4) SKF 525A followed 30 min later by BC. Each cat received the four treatments with two weeks elapsing between consecutive experiments. The frequency of 12 behaviors was scored for 60 min after 1 h posttreatment. BC alone induced emergent behavioral changes (hallucinatory-like, limb flicks, abortive grooms) that were not observed following control injections (vehicle and SKF 525A). There was a complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming induced by BC was significantly reduced. SKF 525A pretreatment was correlated with a significant increase in staring and quiet sitting and a failure of BC to increase activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no changes. The data demonstrated that particular BC-induced changes in cats are antagonized by SKF 525A. The behavioral suppression caused by SKF 525A is compatible with the involvement of active hepatic metabolites from BC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of various pretreatments on the acute nephrotoxic potential of styrene in Fischer-344 rats

The effects of various inducers and inhibitors of hepatic microsomal mixed-function oxidase (MFO) system and diethylmaleate treatment on styrene-induced acute nephrotoxicity in male Fischer-344 rats were studied. Groups of rats were pretreated with either 3-methylcholanthrene (15 mg/kg, i.p., 3 days), or phenobarbital (80 mg/kg, i.p., 3 days), or SKF525-A (50 mg/kg, i.p., 1 h), or piperonyl butoxide (300 mg/kg, i.p., 2 h), or diethylmaleate (400 mg/kg, i.p., 90 min) prior to an i.p. administration of styrene (0, 0.6 and 0.9 g/kg) in corn oil. The uptake of p-aminohippurate (PAH) by renal cortical slices, the morphology of renal cortices, as well as urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GT) of control and pretreated rats were examined 24 h after styrene. The inducers and inhibitors of MFO system failed to modify further the acute nephrotoxicity of styrene. On the other hand, diethylmaleate pretreatment not only reduced further the uptake of PAH, but also produced further significant increase in the urinary excretion of NAG and gamma-GT observed at the higher dose of styrene. Similarly, ultrastructural studies showed a moderate increase in the severity of kidney damage induced at the higher dose of styrene due to pretreatment with diethylmaleate. These data suggest that tissue glutathione concentrations and hence, corresponding conjugating activity might be important determinants of styrene nephrotoxicity. The results further indicate that a metabolic activation system not involving certain cytochrome P-450 might be responsible in styrene-induced nephrotoxicity.