Effects of Plasmodium berghei infection on arteether metabolism and disposition

Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes from rats infected with Plasmodium berghei. The Km for AE was 175.1 +/- 49.1 and 124.4 +/- 115.1 mumol/l, and Vmax was 2.24 +/- 0.45 and 1.22 +/- 0.67 nmol AE formed/mg protein/min in control and infected microsomes (p < 0.05), respectively. Calculated intrinsic clearance (CLint = initial Vmax/Km) for AE was only 4% lower in infected microsomes. Apparent pharmacokinetic parameter estimates for AE using the isolated perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excretion of conjugated DQHS, which is approximately 500-fold higher than free DQHS and 75-fold higher than free AE on a molar basis.     

Evaluation of BTS 67 582, a novel antidiabetic agent, in normal and diabetic rats

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats. 2. BTS 67 582 (3 to 300 mg kg-1, p.o.) caused a dose- and time-dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED50 for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg-1 at 1, 2 and 4 h after administration respectively. 3. In streptozotocin-induced (50 mg kg-1, i.v.) diabetic rats, BTS 67 582 (37-147 mg kg-1, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg-1, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not. 4. BTS 67 582 did not displace [3H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma beta-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the 'sulphonylurea' receptor. 5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg-1 p.o.) and glibenclamide (1 mg kg-1, p.o.) were antagonized by diazoxide (30 mg kg-1, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of KATP channels. 6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.     

Appetite, hunger, and satiety in the elderly

The safety and efficacy of the selective alpha 1-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia were evaluated in a randomized, double-blind and placebo-controlled 9-week study of 100 patients. By patients' overall assessment of voiding difficulties, 79% in the doxazosin group (DG) and 44% in the placebo group (PG) reported improvement (p = 0.001). In the DG, improvement was noted in 63% of obstructive symptoms compared to 32% in the PG (p = 0.015), whereas improvement was noted in 76% and 45%, respectively, of irritative symptoms (p = 0.12). Daytime frequency was reduced by 1.5 in the DG and increased by 0.3 in the PG (p = 0.001), and nocturia was reduced by 1.1 and 1.0, respectively (p = 0.12). Maximum urinary flow rate was improved by 1.5 ml/s in the DG, while it deteriorated by 0.3 ml/s in the PG (p = 0.11). Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity) and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily is safe and effective in relieving symptoms in patients with BPH.     

Extrahepatic first-pass metabolism of nifedipine in the rat

The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after p.o. dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (i.c.), and intraperitoneal (i.p.) routes of administration were compared to that for an intravenous (i.v.) dose (in each case a dose of 6 mg kg-1 was given) using adult male Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after i.v. dosing was 10.3 mL min-1 kg-1. The nifedipine blood-to-plasma ratio was found to be about 0.59. Therefore, the systemic blood clearance of nifedipine was about 17.5 mL min-1 kg-1; which, compared to the hepatic blood flow of rats (55 to 80 mL min-1 kg-1) showed that nifedipine is poorly extracted by the liver (0.22 < or = EH < = 0.32). The mean absolute bioavailabilities of the p.o., i.p., and i.c. doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat.     

Kinetic analysis of propranolol-induced impairment of its own metabolism in rats

The effect of repetitive oral administration of propranolol (100 mg kg-1 day-1, 5 days) on the kinetics of liver microsomal propranolol metabolism was investigated in the rat. Vmax values of the high-affinity phase for biphasic kinetics of propranolol 4- and 5-hydroxylase activities were decreased by propranolol pretreatment, while those of the low-affinity phase were unchanged. The Vmax value of monophasic 7-hydroxylase activity was also decreased. On the other hand, the Vmax value of N-desisopropylase activity in the propranolol-treated rats was increased more than 2-fold compared with non-treated (control) rats, resulting in a change from monophasic in control rats to biphasic kinetics in propranolol-treated rats. These findings indicate that repetitive administration of propranolol selectively impairs a CYP2D isozyme that is involved in the high-affinity phases for propranolol ring-hydroxylations.     

Inhibitory effect of ketamine on depolarization-induced norepinephrine release in the rat ventral hippocampus investigated by in vivo microdialysis

The release of norepinephrine (NE) in the ventral hippocampus was studied in rats with microdialysis method. The basal release of NE with perfusion of normal artificial cerebrospinal fluid (ACSF) was 1.58 +/- 0.37 x 20 microliters-1 sample. The NE concentration increased significantly with perfusion of high potassium (60 mM) ACSF indicating that depolarization-induced release was up to 5 times higher than the basic level. Ketamine (20 mg.kg-1 and 80 mg.kg-1 im) significantly inhibited the depolarization-induced increase of NE, but did not affect the basal release. Neither 5 mg.kg-1 im of ketamine nor MK-801 had any effect on the basic or the depolarization-induced release. These results suggest that the inhibitory effect of ketamine on the depolarization-induced NE release was not due to the NMDA channel blocking properties of ketamine.     

Fluorescent labelling of abasic sites: a novel methodology to detect closely-spaced damage sites in DNA

We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosolic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (> 20% body weight loss) was found by day 6 of the infusion. Steady-state plasma IUdR levels were 1.0-1.2 microM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-min) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.     

Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents

The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.     

Failure of postexposure treatment of rabies in children

In the female mouse, dapsone (50-500 mg kg-1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0.5-1 h with recovery to baseline values occurring by 4 h. Cimetidine (100 mg kg-1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg-1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 mg kg-1, p.o. daily). It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.     

Effect of litter moisture and brooding temperature on body weights of turkey poults experiencing poult enteritis and mortality syndrome

Radioprotective and therapeutical effect of silymarin (Flavobion) on development and repair of latent injury in rat liver was examined by its application during the continual gamma irradiation (dose rates 0.2 and 0.6 Gy/day) or after acute gamma irradiation (dose 6 Gy). Silymarin influence was evaluated on the basis of mitotic index and chromosomal aberration frequency in the liver regenerating after partial hepatectomy. We have found that silymarin application stimulates the process of liver regeneration in non-irradiated rats as well as in irradiated ones. Positive effect of silymarin (100 mg per kg p.o. ones per day) was manifested at both dose rates of continual irradiation with increase in mitotic activity and mitigation of chromosomal erration frequency in the regenerating liver in comparison with non-protected irradiated animals. Curative effect of silymarin (70 mg/kg p.o., twice per day) was shown especially after 14 days of its postradiation application.     

Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence

Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.     

Alpha-fetoprotein and chromosome aberrations: what else? Results of a prospective study concerning 15,533 pregnancies

Gastric lesions induced by indomethacin (20 mg.kg-1 i.p.) were studied in rats after a 24 hour fast. The size of the lesions was correlated with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v administration) and with the rate of gastric emptying (determined from the phenol red concentration after its intragastric application). These changes were correlated with the prevention of gastric lesions by allopurinol (50 mg.kg-1) after a single dose or once daily for 3 days before indomethacin and by a single dose (15,000 U.kg-1) of superoxide dismutase (SOD). Indomethacin significantly increases the rate of gastric emptying concomitantly with gastric vascular permeability. The pretreatment of animals with allopurinol and SOD inhibits gastric lesions as well as gastric vascular permeability without changing gastric emptying which was increased after indomethacin administration. The inhibition of gastric lesion formation and gastric vascular permeability was more marked in rats pretreated with allopurinol for 3 days when compared with rats treated with a single dose of allopurinol only. These results support the suggestion that oxygen-derived free radicals contribute to the pathogenesis of indomethacin-induced gastric lesions.     

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

1. Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down-regulation has been reported to occur upon chronic administration of conventional BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD partial agonist, and diazepam in rats. 2. After acute administration, imidazenil was more potent though less effective than diazepam in protecting from bicuculline-induced seizure. The time-course analysis of two peak equieffective doses of imidazenil (2.5 mumol kg-1 p.o.) and diazepam (35 mumol kg-1, p.o.) showed a longer lasting action of the former drug. 3. The anticonvulsant efficacy of diazepam (35 mumol kg-1, p.o.) was reduced in rats given chronic diazepam (35 mumol kg-1 p.o., 3 times a day for 8-15 days). No tolerance to imidazenil (2.5 mumol kg-1, p.o.) was apparent after 130-day administration with imidazenil (2.5 mumol kg-1, p.o., 3 times a day). 4. Plasma levels of imidazenil and diazepam, assessed 30 min after administration, were not changed in chronically treated animals. 5. In rats made tolerant to diazepam, the maximum number of [3H]-flumazenil binding sites were reduced in both cerebral cortex (-36%) and cerebellum (-42%). No changes in [3H]-flumazenil binding were found in chronic imidazenil-treated rats. 6. Specific [3H]-flumazenil binding in vivo was decreased in the forebrain of chronic diazepam- but not of chronic imidazenil-treated animals. 7. These data indicate that imidazenil possesses a very low tolerance potential to its anticonvulsant activity and does not affect BZD receptor density even after prolonged administration.     

Effect of the separate and combined administration of mestranol and phenobarbital on the development of altered hepatic foci expressing placental form of glutathione S-transferase in the rat

The stages in the carcinogenesis process include initiation, promotion and progression. Although many characteristics of tumor promotion and promoting agents have been reported, relatively few studies on the effects of combinations of promoting agents have been detailed. For study of the combined effects of phenobarbital (PB) and mestranol (MS) in multistage rat hepatocarcinogenesis, an initiation-promotion protocol was developed. Female rats were injected i.p. at 5 days of age with either diethylnitrosamine (DEN) (10 mg/kg) or the solvent tricaprilyn. At weaning, approximately 10 rats from both the DEN-initiated and the solvent control groups were provided basal diet alone, PB (10, 100 or 500 mg/kg diet), MS (0.02 or 0.2 mg/kg diet) or various combinations of both PB and MS in the basal diet. At 8 months of age, the rats were killed and the livers removed, sectioned and fixed in ice-cold acetone. Sections of 5 microgram thickness were stained for placental glutathione S-transferase (PGST) expression, and the volume fraction of liver occupied by altered hepatic foci was determined by stereology. In addition, incorporation of bromodeoxyuridine into nuclei of PGST-expressing (focal) and non-PGST-expressing (non-focal) hepatocytes was determined. Administration of the highest dose of PB resulted in a significant decrease in non-focal hepatocyte labeling index, with a 4-fold differential between the focal and non-focal hepatocyte labeling index. Administration of 0.2 mg/kg diet MS resulted in effective promotion. The non-focal labeling index was increased and the focal labeling index was further enhanced (3-fold) relative to the non-focal index by this dose of MS. Combination of the lower MS dose with PB resulted in at least an additive promoting effect; however, a lower volume fraction was noted for the combination of low MS dose plus the highest PB dose. Combination of the higher MS dose with PB resulted in an elevation of volume fraction only for the middle PB dose. These findings indicate that the potency of promotion by mixtures is modulated by the dose of each component as well as by pharmacodynamic and pharmacokinetic properties of each component of the mixture.     

Homogeneous or heterogeneous distribution of systemically administered adrenaline: organ dependence

In incubation experiments it was shown that exogenous adrenaline or noradrenaline does not distribute homogeneously into the adrenergic varicosities of the rat vas deferens (wall with thick and compact muscle layer) but does distribute homogeneously in the rat spleen capsule (thin and loose muscle layer, containing more extracellular space than the vas deferens). To circumvent any hypothetical role of the muscular layer in the distribution of the amine, 100 micrograms.kg-1.h-1 adrenaline was administered to rats in vivo either i.v. (during 90 min) or i.p. (under pentobarbital anaesthesia, an Alzet minipump was implanted which delivered that dose during 6 days). The rats also received 100 mg.kg-1 pargyline (to inhibit MAO) and 100 mg.kg-1 tropolone (to inhibit COMT). At the end of adrenaline administration, vasa deferentia and spleen capsule were removed, washed and then exposed to 100 mumol.l-1 tyramine for 20 min. At the end of this exposure, the ratio noradrenaline/adrenaline in the tissue and in the medium was compared. In the vas deferens both after i.v. and i.p. administration of adrenaline, the ratio noradrenaline/adrenaline was about 3 times higher in the medium than in the tissue, while in the spleen capsule the ratio noradrenaline/adrenaline was not significantly different in the medium and in the tissue. We conclude that, even when the amine reaches the storage sites from the blood, it distributes homogeneously in the spleen capsule and heterogeneously in the vas deferens, perhaps because there are more than one kind of storage vesicles in the vas deferens.     

Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats

The purpose of this study was to establish a nude rat orthotopic (organ-specific) human colorectal cancer model as an in vivo secondary screen for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in clinical]. After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growth and invasion to both the mucosal and the serosal sides were observed in all rats. Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them. Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14 consecutive days from 7 days after tumor cell implantation. S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When both drugs were administered to nude rats bearing KM12C injected into the cecal wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05). After the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase inhibition rate (percentage) in the tumor (about 20%). Collectively, these findings suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.     

Translactational induction of CYP4A expression in 10.5-day neonatal rats by the hypolipidemic drug clofibrate

Lactating mothers of 7.5-day neonatal rats were injected intraperitoneally with 500 mg kg-1 clofibrate for 3 consecutive days at 24-hour intervals; 24 hours after the final injection, the maternal cytochrome P450 4A (CYP4A) mRNA levels had risen 14- and 2.5-fold above the constitutive levels of expression seen in the liver and kidney, respectively. Lactational transfer of clofibrate to the suckling 10.5-day litter was demonstrated by the 15- and 5-fold elevation observed in the neonatal hepatic and renal CYP4A mRNAs, respectively, following suckling from drug-induced mothers. A significant decrease in the relative liver weights of these neonatal pups was seen following clofibrate exposure via maternal milk, in total contrast to the normally observed increase in liver/body weight ratios of rats treated with clofibrate. Western blot analysis using a polyclonal goat anti-rat CYP4A1 antibody also demonstrated a rise in the CYP4A protein levels in both the mothers and their litters following maternal clofibrate treatment.     

Development of hydroxysteroid sulfotransferase-deficient lesions during hepatocarcinogenesis in rats

Rat liver cytosolic hydroxysteroid sulfotransferases form highly reactive sulfuric acid esters from some benzylic alcohols, such as 1-hydroxymethylpyrene. In this study we examined the expression of hydroxysteroid sulfotransferase a (STa) in carcinogen-induced enzyme-altered, presumably preneoplastic, rat liver foci. Female Wistar rats were given a single i.p. injection of diethylnitrosamine (0.15 mumol/g body wt) 1 day after birth to induce the liver foci. After weaning, rats were given 1-hydroxymethylpyrene or phenobarbital continuously in their diet (250 or 500 p.p.m. respectively) for a total of 120 days. Carcinogen-induced liver foci were identified by a change in the marker enzyme adenosine triphosphatase. Immunohistochemical staining of consecutive sections using an anti-STa rabbit antibody demonstrated that STa was expressed at decreased levels in most of the adenosine triphosphatase-negative liver foci. This effect was observed in both 1-hydroxymethylpyrene- and phenobarbital-treated animals. The decrease in STa content in enzyme-altered foci may lead to a selective advantage of the preneoplastic cells in the presence of agents that are able to form reactive sulfuric acid esters, such as 1-hydroxymethylpyrene. In some diethylnitrosamine/phenobarbital-treated rats, a small number of atypical foci were observed, most of them showing enhanced expression of STa and unchanged to moderately increased ATPase activity.     

Time course of enzyme induction in liver and kidneys and absorption, distribution and elimination of 1,4-dichlorobenzene in rats

Time course of enzyme induction was measured in Fischer344 rats treated daily at 150 and 600 mg 1,4-dichlorobenzene (1.4-DCB)/kg p.o. up to 28 days. The monoxygenases 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and aldrin epoxidase (ALD) as well as the phase II enzymes; epoxide hydrolase (EH), glutathione S-transferase (GS-T) and glucuronyl transferase (GLU-T) were dose-dependently induced in the liver of males and females. A pronounced induction in the kidneys was measured at 600 mg/kg only for ECOD. After single oral administration of 100 and 1000 mg/kg bw and feeding of 100 and 1000 ppm (corresponding to approximately 10 and 100 mg/kg bw) to male Wistar rats for 28 days, the time course of 1,4-DCB and 2,5-DCP concentrations was investigated in plasma, adipose, hepatic and renal tissue. In addition, total urinary excretion of 2,5-DCP was determined. After single application, 1,4-DCB and 2,5-DCP were rapidly eliminated from the plasma and tissues, 40-60% of the dose administered was excreted as 2,5-DCP in the urine. There were no indications of cumulative effects after a feeding period of 28 days. The concentrations decreased in all tissues until the 7th day of study. Thereafter, there seems to be a steady state until the 28th day. A total of 7 days after the end of exposure, no more residues could be detected. Following long-term inhalation (450 and 3000 mg/m3) 1,4-DCB concentrations were highest in adipose tissues at 6 months followed by a marked decline at 18 months. 1,4-DCB and 2,5-DCP concentrations in plasma and liver were much lower but again with a peak at 6 months. When compared with published human data on measurements in plasma, urine, liver and adipose tissue the results suggest that there should be no hazard for the general population.     

Subchronic Toxicity of Lanthanum Nitrate on Liver in Rats

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