Effect of dibromotetrafluoroethane inhalation on hepatic drug metabolism in mice

Inhalation of dibromotetrafluoroethane, 0.63 to 1.0%, for 5 hr daily, for 3 or 4 days, reduced hexobarbital sleeping time and zoxazolamine paralysis time 2-fold in mice. Increased metabolism of hexobarbital and zoxazolamine by the hepatic 9000 g microsomal supernatant fraction prepared from exposed mice correlated well with the effects determined in vivo. Addition of 2,4-dichloro-6-phenyl-phenoxyethyldiethylamine (SKF 525-A) to the hepatic 9000 g microsomal supernatant fraction prevented the dibromotetrafluoroethane-induced increase in hepatic drug metabolism.     

Effects of carbon monoxide exposure on the distribution of methylmercury in mice

Effects of long-term exposure to sublethal concentration (300-350 ppm) of carbon monoxide (CO) on the distribution of methylmercury (MeHg) in the blood and organs of mice were examined using 6th week-old ICR mice of both sexes. Firstly, female mice were exposed to CO immediately after single ip injection of CH3HgCl (1 mg/kg). At the earliest stage, brain mercury level was higher in CO mice than in control mice, while blood mercury level was lower in CO mice than in control mice. There were indications that compensatory hemoconcentration and resultant increase of mercury levels in the blood, brain and liver occurred in CO mice by the 8th day of CO exposure. Mercury in the blood, brain, liver and kidney decreased more rapidly in CO mice than in control mice for a short period after hemoconcentration had occurred. Secondly, male mice were pre-exposed to CO for 7 days, received single ip injection of CH3HgCl (1 mg/kg) and were re-exposed to CO for an additional 21 days. Hemoconcentration, increased mercury levels in the blood, brain and liver were observed in CO mice. Thirdly, male mice were pre-exposed to CO for 7 days, administered po with CH3HgCl (2 mg/kg) and re-exposed to CO for 24 hr. Mercury levels in the blood, brain and liver but not the kidneys were higher in CO mice than in control mice. The relationships between hemoconcentration and MeHg distribution in vertebrates were discussed.     

Effect of intermittent carbon monoxide inhalation on erythropoiesis and organ weights in rats

Sprague-Dawley rats were exposed to 450 ppm carbon monoxide (CO) for 6 h per day, 5 days per week for 33 days. The effect of CO on reticulocyte count, hematocrit, hemoglobin concentration, body weight and selected organ weights was measured. Exposure to CO caused a three-fold increase in the youngest reticulocyte population, concomitant with an increase in the total reticulocyte count. Despite continued CO exposure, reticulocyte number and distribution returned to normal by day 9, suggesting that reticulocyte response of the organism to CO had changed. Both hematocrit and hemoglobin concentrations began to increase 16 days after CO exposure and remained at the increased level for the duration of the exposure period. There were no changes in kidney, liver and adrenal weights throughout the course of study. However, spleen weight was increased after 5 days of CO exposure. Left and right ventricular organ weight ratios increased equally at the same time during the study. These results indicate that the increase in the young reticulocyte population and the subsequent increase in total reticulocyte count are the earliest erythropoietic responses to intermittent CO exposure and that CO-induced polycythemia is associated with cardiac hypertrophy in rats.     

Interferon reduces hepatic drug metabolism in vivo in mice

The effects of two highly purified human leukocyte interferons (IFN-A and IFN-AD) on drug-metabolizing capacity in mice have been investigated. IFN-AD was found to produce significant changes in antipyrine half-life, assessed by analysis of 14CO2 exhalation rates following 14C-antipyrine administration. By contrast, IFN-A, which has considerably less antiviral potency than IFN-AD, was found to have no effect on antipyrine half-life. The administration regimen was found to markedly alter the effects seen with IFN-AD. When IFN-AD was given as single daily doses (5 X 10(7) units/kg/day X 3 days), the half-life of antipyrine increased by a mean of 40% (from 21.0 to 28.9 min). However, when a smaller daily dose (3 X 10(7) units/kg/day) was given as a continuous infusion, the antipyrine half-life increased by more than 3-fold (from 20.8 to 68.5 min) after 3 days of administration. Continued infusion for a further 3 days produced no additional change in antipyrine half-life. These results demonstrate that human leukocyte interferons can significantly inhibit hepatic metabolic activity in vivo.     

Neurotoxicologic evaluation of rats after 13 weeks of inhalation exposure to dichloromethane or carbon monoxide

Male and female Fischer 344 rats were exposed to dichloromethane (methylene chloride, DCM) or carbon monoxide (CO) for 6 hr/day, 5 days/week, for 13 weeks. Since oxidative metabolism of DCM to CO and CO2 is a saturable process, DCM exposure concentrations were selected clearly below saturation (50 ppm), just below saturation (200 ppm), and well above saturation (2000 ppm). At saturation of metabolism, metabolic CO causes about 10% carboxyhemoglobinemia (COHb). Therefore, as a control for CO effects, a separate group of rats was exposed to 135 ppm CO to induce approximately 10% COHb. Postexposure functional tests included an observational battery, hindlimb grip strength, and a battery of evoked potentials (flash, auditory brainstem, somatosensory, caudal nerve). After functional tests were completed, rats from all groups were perfused with fixative and a comprehensive set of nervous tissues from the high DCM exposure group and from controls were examined by light microscopy. Although some miscellaneous functional and morphologic variations were recorded, none were related to treatment. Thus, subchronic exposures as high as 2000 ppm DCM or 135 ppm CO had no deleterious effects on any of the measures of this study.     

Effects on the offspring of chronic low exposure carbon monoxide during mice pregnancy.

This research is primarily concerned with the effects of chronic low doses of carbon monoxide on fetal development. Carbon monoxide was administered daily by inhalation to female Swiss Webster mice from the beginning of gestation until term. Daily weights were recorded and carbon monoxide blood levels determined every 4 days. The number of offspring in each litter was recorded. At weaning, two males and two females from each litter were randomly picked for maze running studies. When the mice were 6 weeks old, they were tested daily, ten trials per day, in the maze until learning had occurred. The number of days required to learn the maze and the number of incorrect trials were recorded. While there was no significant increase in the number of days needed to learn the maze, there was a significant increase in the number of errors made by the experimental group during this time. This indicated that an increased effort was needed to learn the maze.     

Effect of acute carbon monoxide exposure on cardiopulmonary function of the awake rat

Unanesthetized male Sprague-Dawley rats were exposed for 20 min to 0 (control), 2000, or 4000 ppm carbon monoxide, and cardiopulmonary responses were evaluated. Venous blood samples were taken prior to exposure and at 2, 4, 7, 11, 15, and 20 min during exposure. Responses for CO-exposed animals were compared at 20, 30, 40, 50, and 60% carboxyhemoglobin (COHb), and these values were compared to control values at similar times during exposure. Fifty percent COHb was attained within 4 to 8.5 min at 4000 ppm and 11 to 14 min at 2000 ppm. For both CO exposure groups, mean arterial pressure first decreased at 40% COHb and fell to 69% of baseline at 60% COHb. Tidal volume and breathing frequency increases resulted in minute volume elevations of 52 (2000 ppm) and 77% (4000 ppm) at 60% COHb. Minute volume was elevated at 50 and 60% COHb at 4000 ppm, but was not elevated until 60% COHb for 2000-ppm exposures. The earlier ventilatory stimulation at 4000 ppm may have been a by-product of increased agitation observed in rats exposed to the higher concentration.     

Effect of cold exposure on drug action and hepatic drug metabolism in the rat

Exposure of male rats to a temperature of 4°C for 4 days decreased the sleeping time response to hexobarbital and meprobamate, but not to barbital. Plasma concentrations of these drugs present at the time the righting reflex was regained were lower in the cold-exposed rats, indicating that the observed decrease in sleeping time was not due to decreased central nervous system sensitivity to these agents. The onset time of hexobarbital, meprobamate and barbital hypnosis was similar in cold-exposed and control rats, suggesting that altered drug absorption is not responsible for the observed differences in duration of drug response. The decline of brain and plasma concentrations of zoxazolamine was more rapid in the cold-exposed animal. The metabolism of hexobarbital and aminopyrine was significantly elevated in isolated perfused livers from cold-exposed rats. Hepatic microsomal N-demethylase activity, hexobarbital and meprobamate oxidation, CO-binding pigment, and NADPH-cytochrome c reductase activity were increased in the cold-exposed rat. Experiments with 2-¹⁴C-glycine indicated that the in vivo incorporation of this isotope into hepatic microsomes was increased significantly in the cold-exposed rat. These results indicate that cold exposure stimulates hepatic drug metabolism and suggest that this stimulation is mediated via an accelerated synthesis of the hepatic drug-metabolizing system.     

甘草对药物代谢酶以及化学药物体内代谢的影响

甘草对肝细胞色素P450(CYP450)酶活性具有诱导或抑制作用,对一些化学药物如氨茶碱、安替比林、丙米嗪、利多卡因、氯沙坦等的体内代谢产生影响,合用时使这些药物的药物代谢动力学发生改变,在临床应用过程中应注意。因此,需要进一步在人体内研究甘草提取物及其有效成分与其他药物的相互作用。从CYP450酶角度研究中药,有利于从分子水平探讨中药的作用机制或毒性机制,并有可能揭示中药之间或中药与西药产生相互作用的关系,防止临床配伍用药后的不良反应,从而提高中药临床应用的有效性与安全性,促进临床合理用药。本文综述了甘草对药物代谢酶以及化学药物体内代谢的影响。     

Effects of prenatal carbon monoxide exposure on cardiac development

Biochemical assays and weight measurements were made to determine the basis for the cardiomegaly which has been reported following chronic carbon monoxide (CO) exposure. Long Evans rats bred in the laboratory were exposed throughout gestation either to room air or air containing 150 ppm CO. The exposure terminated within 12 hr after parturition. CO-exposed neonates showed persistent body weight depression throughout the preweaning period. Wet heart weight was elevated in the CO-exposed rats at birth, but no difference between groups remained at 4 days of age. Dry heart weight did not differ significantly between groups at birth. Biochemical analyses conducted at 1 day of age suggested a general reduction in concentration of protein as well as DNA, RNA, and free nucleotides although none of these differences was statistically significant. Total content of these cellular constitutents was not significantly affected by the prenatal CO exposure despite the increased wet weight of the heart. It is concluded that increased water content accounted for the increased heart weight seen at birth in CO-exposed rats.     

疾病对药物体内代谢过程的影响

疾病可影响药物在体内的吸收、分布、代谢和排泄过程。本文基于Medline发表的相关研究,重点介绍短肠综合征、囊性纤维化和肝胆疾病等对药物体内代谢过程的影响。短肠综合征和囊性纤维化都显著影响药物的吸收和肠肝循环,而肾病、胆囊炎或胆囊手术可能影响药物的排泄。肝病影响药物代谢的肝药酶(P450同工酶)。疾病对药物代谢的影响,可能导致药物治疗无效或者中毒,引起严重后果。因此临床应该了解疾病对药物代谢影响的基本知识,治疗中主动调整给药方法和剂量,提高药物治疗效率,减少药源性的损害。     

Effects of carbon monoxide inhalation on erythropoiesis and cardiac hypertrophy in fetal rats.

Pregnant rats were exposed to four CO concentrations over 21 days, and the effects of CO on fetal hemoglobin, hematocrit, heart weight, and body weight were measured. The exposure to 250 and 500 ppm of CO caused a sharp depression in fetal hemoglobin and hematocrit, coincident with a marked reduction of the weight of the fetuses, indicating a high vulnerability to CO of both fetal erythropoiesis and growth. The concentration of 125 ppm of CO did not affect fetal red blood cells, while 60 ppm of CO caused a slight increase in hematocrit. This low dose is below the threshold of an adaptive response in adult animals. The hearts of the fetuses exhibited a large increase in weight, which was even present in the 60-ppm group in contrast to reported data for adult animals. Since a severe anemia rather than polycythemia occurred, an increased blood viscosity cannot be responsible for the hypertrophic heart of the fetuses and consequently also of the adult animals, if the principal mechanisms for heart growth are identical in fetuses and adult animals. It is further unlikely that pulmonary hypertension causes the cardiac hypertrophy because the fetal lung circulation is only slightly developed. The reason of the heart weight increase therefore remains unknown.     

Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo

OBJECTIVE: To study the effects of methylprednisolone on the pharmacokinetics and pharmacodynamics of triazolam. METHODS: In this three-phase cross-over study, ten healthy subjects received 0.25 mg oral triazolam on three occasions: on day 1 (no pretreatment, control), on day 8 (1 h after a single dose of 32 mg oral methylprednisolone) and on day 18 (after further treatment with 8 mg oral methylprednisolone daily for 9 days). The plasma concentrations of triazolam were determined up to 10 h, and its effects were measured using four psychomotor tests up to 6 h. RESULTS: The single dose of methylprednisolone showed no significant effects on the pharmacokinetics of triazolam. However, the Digit Symbol Substitution Test result was better (P < 0.05) during the single-dose methylprednisolone phase than during the control phase, the other three tests showing no differences between the phases. The multiple-dose treatment with methylprednisolone reduced the mean peak plasma concentration (Cmax) of triazolam by 30% (P < 0.05) but had no significant effects on the time to Cmax (tmax), elimination half-life (t 1/2), area under the plasma concentration-time curve from 0 h to 10 h (AUC(0-10 h)) and AUC(0-infinity) and did not alter the effects of triazolam. CONCLUSION: A single, relatively high dose of methylprednisolone (32 mg) did not affect cytochrome P450 (CYP)3A4 activity, and treatment with 8 mg methylprednisolone daily for 9 days did not result in clinically significant induction of CYP3A4.     

Complex maze performance during carbon monoxide exposure in rats

Most human victims of residential fires die of smoke inhalation. The cause of death of the victims is attributed to high levels of carboxyhemoglobin, but it is not clear why the victims are unable to escape even from locations remote from flaming combustion. In an attempt to provide a model of escape from toxic gases using animals, a complex maze was built for rats with 8 choice points. The animals were 24 hr water deprived and trained to remain in the start box for 15 min. Following this period, a rat was released in the maze and had to learn to avoid blind alleys and reach the goal box for water reinforcement within 15 min. Total time to traverse and total distance in the maze were recorded. Each animal was given one trial per day. After stable running times were established, different groups of six rats were exposed to 2000, 3000, 3500, and 4000 ppm of carbon monoxide (CO) when placed in the maze. Each animal was exposed to CO only once. On the day after CO exposure the rats were implanted with an arterial cannula and on the next day each animal was exposed to the same CO concentration it had previously experienced for 30 min. Blood samples were taken every 5 min. The effect of increasing CO concentrations was to increase maze running times as well as to decrease the number of animals reaching the goal. At 3500 ppm no animal reached the goal. At 2000 ppm, the animals that failed to reach the goal moved a greater distance than animals that reached the goal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Formulas predicting carboxyhemoglobin resulting from carbon monoxide exposure

A microcomputer program in BASIC for predicting the percent carboxyhemoglobin of blood in men exposed to carbon monoxide is designed. Formulas used in this program are derived from the data reported by Forbes, Sargent and Roughton. A general formula previously published by the author expresses the mathematical relationship among the intensity of a stressor, the time of exposure, and the occurrence of a biological response. This formula is implemented in this study, using carbon monoxide as the specific stressor. Analysis of the reported and the computer-assisted predicted data has shown that the program for the constructed formulas is fairly accurate and reliable in expressing carboxyhemoglobin as a function of the air CO concentration and the time of exposure. The predictive formulas can determine the relationship among the carbon monoxide concentration in air, the time of exposure, and the percent carboxyhemoglobin level of blood, and may be of value in industry, in environmental protection and in medicine.     

Chlorodibromomethane metabolism to bromide and carbon monoxide in rats

The chlorodibromomethane (CDBM) metabolites bromide and CO were analysed as bromide level in plasma and carboxyhaemoglobin (COHb) level in blood of rats, respectively. The mean basic levels of bromide in plasma of rats receiving vehicle were 0.075 ± 0.036 mmol/l (n = 27). After administration of CDBM at 0.4, 0.8, 1.6, and 3.1 mmol/kg p.o., the mean bromide levels rose to maximal values that were higher by a factor 27, 48, 69, and 135, respectively. Bromide elimination was slow and the plasma level was significantly increased following repeated administration in comparison to a single administration of CDBM. The CDBM concentrations in blood and in fat tissue 6 h after the last of 7 administrations of 0.8 mmol CDBM/kg p.o., once a day for 7 consecutive days, were significantly lower than 6 h after a single gavage of this CDBM dose. The mean normal level of 0.45 ± 0.32% COHb in rats (n = 30) was significantly increased following oral CDBM uptake. Initially higher COHb levels were measured after 7 consecutive applications of 0.8␣mmol/kg CDBM. After a single administration of CDBM the level of glutathione disulphide in the liver was significantly increased; this effect was reversible. The oxidative CDBM metabolism was influenced by the glutathione (GSH) concentration in the liver. The rate of COHb and bromide formation was decreased after GSH depletion due to pretreatment of rats with buthionine sulphoximine (BSO) and increased following enhancement of the GSH concentration due to pretreatment of the animals with butylated hydroxyanisole (BHA). CDBM is a substrate for cytochrome P-450 2E1 (CYP2E1), as demonstrated by the inhibition of bromide and COHb formation due to simultaneous administration of CDBM and the CYP2E1 inhibitor diethyldithiocarbamate (DDTC); also by the initially higher levels of bromide in plasma and COHb in blood after gavage of CDBM pretreated with isoniazid (INH), an inducer of CYP2E1. The increase of bromide formation after CDBM administration in phenobarbital (PB)-pretreated rats indicated that cytochrome P-450 2B1 and 2B2 (CYP2B1 and CYP2B2) play a role as catalysts of the CDBM biotransformation. It is shown that m-xylene pretreatment, which activates CYP2E1 as well as CYP2Bs, leads to a higher bromide level after CDBM administration than the INH or PB pretreatment. In liver microsomes of rats treated with CDBM (0.8 mmol/kg p.o., seven daily applications), the p-nitrophenol hydroxylase (p-NPH) activity, a marker of CYP2E1, was increased. It is concluded that CDBM may be an inducer of CYP2E1. These results combined with literature data demonstrate that the oxidation of CDBM was catalysed mainly by CYP2E1 and CYP2Bs and that there may be a risk of bromide accumulation following repeated uptake of the trihalomethane. Received: 15 May 1996 / Accepted: 5 September 1996