High-density lipoprotein subfractions,apolipoproteins and antipyrine clearance in normal subjects

Summary Serum high density lipoprotein (HDL) subfractions HDL₂ and HDL₃, apolipoproteins, and plasma antipyrine clearance (AP-CL) rate, an index of liver microsomal enzyme activity, were determined in 21 healthy subjects. High HDL cholesterol and HDL₂ cholesterol concentrations and HDL cholesterol/cholesterol and HDL₂/HDL₃ cholesterol ratios were associated with high AP-CL. Phenobarbital enhanced antipyrine elimination and increased the apolipoprotein A-I/A-II ratio. Subjects who had high AP-CL had a more antiatherogenic HDL subfraction and apolipoprotein profile than those with low AP-CL.     

Plasma high-density lipoproteins and hepatic microsomal enzyme induction

Summary The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal liver. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HDL. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.The results have been presented at the annual meetings of the American Society for Clinical Pharmacology and Therapeutics, Kansas City, Missouri, 21–23 March 1979 [24] and the Scandinavian Society for Atherosclerosis Research, Turku, Finland, 31 August-1 September 1979 [23]     

Microsomal enzyme induction, lipoproteins and atherosclerosis

The liver is the principal site for the synthesis and elimination of lipoproteins circulating in plasma, and alterations in hepatic function influence plasma lipoprotein levels. High HDL-C/T-C and apo A-I/apo B ratios, which are characteristic of a low coronary risk, have been typical of healthy subjects with high microsomal enzyme activity in the liver. Microsomal enzyme inducing drugs such as phenytoin, phenobarbital and carbamazepine, and also alcohol, influence serum lipid and apoprotein concentrations. The inducers increase the concentrations of hepatic microsomal enzyme and apo A-I mRNA, and also proteins and phospholipids. They similarly increase serum HDL-C and apo A-I levels and the HDL-C/LDL-C ratio, powerful protective factors against coronary heart disease. These parameters parallel hepatic protein and phospholipid concentrations, and microsomal enzyme activity as assessed by liver cytochrome P-450 or antipyrine kinetics. Serum LDL-C levels are inversely proportional to hepatic cytochrome P-450 concentrations. Experimental studies indicate that phenobarbital retards cholesterol accumulation in the arterial wall and the formation of atherosclerotic plaque. A decreased mortality rate from coronary heart disease has been reported for subjects who take enzyme inducers, drugs or alcohol, whereas impairment of hepatic microsomal function may promote atherogenesis. In addition to drugs non-pharmacological factors such as dietary constituents and physical exercise may influence hepatic microsomal function and hence improve the serum lipoprotein profile. These observations, which connect microsomal inducers, liver lipids and proteins, serum lipids and apoproteins characteristic of a low risk of atherosclerotic disease and low incidence of coronary deaths, lead to the conclusion that the activation of liver microsomal function can prevent atherogenesis in man.     

Serum low-density lipoprotein and high-density lipoprotein cholesterol,and liver size in subjects on drugs inducing hepatic microsomal enzymes

Summary Serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentration and the ratio between them, major risk factors of coronary heart disease, and liver size were investigated in 18 subjects who were on enzyme-inducing anti-convulsants, phenytoin alone or in combination with phenobarbital and/or carbamazepine. The subjects with a high liver cytochrome P-450, indicating hepatic microsomal enzyme induction, who showed an increase in liver size, had an elevated high-density lipoprotein concentration and high-density lipoprotein cholesterol/total cholesterol ratio, and a reduced low/high-density lipoprotein cholesterol ratio. The high-density lipoprotein cholesterol concentration and its ratio to total cholesterol were directly and related to the ratio between low and high-density lipoprotein cholesterol were inversely related to the extent of liver enlargement. The serum cholesterol distribution profile associated with an increase in liver size was typical of subjects with a low risk of coronary heart disease. The results suggest that enzyme-inducers, such as phenytoin and phenobarbital, induce structural and functional changes in hepatocellular membranes associated with liver enlargement and cholesterol distribution characteristic of low susceptibility to atherosclerotic vascular disease.     

Relationship between plasma high-density lipoprotein cholesterol and anticonvulsant levels in epileptics

Plasma high-density lipoprotein (HDL) cholesterol is a recognized negative risk factor for coronary heart disease. In this study, therapy with phenytoin alone, carbamazepine alone, and phenytoin in combination with phenobarbital was associated with elevated plasma HDL cholesterol concentrations. The highest HDL cholesterol levels were seen in subjects treated with the combination of phenytoin and phenobarbital. Plasma HDL cholesterol levels were proportional to the serum phenobarbital and carbamazepine concentrations. In subjects treated with phenytoin alone, low plasma HDL cholesterol levels were associated with low drug concentrations. The results suggest direct links running from the serum anticonvulsant levels to the extent of hepatic microsomal enzyme induction, and further to the plasma HDL cholesterol concentrations.     

Large theophylline requirements due to high theophylline clearance: verification by the antipyrine test

An asthmatic patient required very high doses of theophylline (2.88 g/day by intravenous infusion) to maintain an adequate serum theophylline concentration (12 micrograms/ml). His cigarette smoking and concurrent treatment with phenytoin were suspected to have produced hepatic microsomal enzyme induction, causing unusually high theophylline clearance. The intravenous antipyrine test demonstrated an unusually short half-life (5.5 h) and high clearance (95 ml/min) of antipyrine, consistent with induced clearance of antipyrine. Formation of the 4-hydroxy metabolite of antipyrine was disproportionately induced. Thus the antipyrine test can be of clinical value for documenting hepatic microsomal enzyme induction in patients with low steady-state theophylline concentrations despite high maintenance doses.     

The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man.

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.     

ENZYME INDUCTION BY EATING CHARCOAL-GRILLED STEAK WITH NO EFFECT ON BLOOD LIPIDS

1. There has been interest in the suggestion that enzyme-inducing drugs, such as anticonvulsants, may produce beneficial changes in lipoprotein levels, in particular a rise in the ratio of high density lipoprotein cholesterol to total cholesterol. 2. This controlled study observed the effects of diets of charcoal or oven-cooked beef on antipyrine clearance (a commonly used measure of drug metabolizing capacity), the apparent oral clearance of phenacetin (a measure of cytochrome P448-dependent enzyme activity) and blood lipids in 18 healthy volunteers. 3. Charcoal-cooked beef increased antipyrine clearance by an average of 20% (P less than 0.059) and increased the apparent oral clearance of phenacetin fivefold (P less than 0.01). In contrast, oven-cooked beef did not significantly alter either measure of microsomal function. Neither diet had any effects on blood lipids. 4. We conclude that the type and degree of enzyme induction achieved by this type of dietary manipulation does not produce beneficial changes in lipoprotein profiles. A previously noted rise in high density lipoprotein cholesterol levels in volunteers fed charcoal-cooked beef may have been due to the effects of charcoal formed by charring of the beef during cooking.     

Gene Activation,Apolipoprotein A-I/High Density Lipoprotein,Atherosclerosis Prevention and Longevity

Abstract: Recent studies in man and human apolipoprotein A-I transgenic animals emphasize the significance of apolipoprotein A-I and high density lipoprotein in antiatherogenesis. Several drugs and other compounds, e.g. phenobarbital, gemfibrozil, fenofibrate, prednisone, estrogen and alcohol, induce apolipoprotein A-I synthesis. They commonly produce serum lipoprotein patterns typical of a low risk of coronary heart disease, and many of them have been found to prevent atherogenesis, reduce coronary heart disease mortality and increase survival. These compounds act against atherosclerosis by using one or several mechanisms that include overexpression of the apolipoprotein A-I gene with an increase in serum apolipoprotein A-I and high density lipoprotein and promotion of reverse cholesterol transport, upregulation of the low density lipoprotein receptor gene with a decrease in serum apolipoprotein B and low density lipoprotein, maintenance of endothelial cell function and protection against thrombosis. They have been found to raise high density lipoprotein cholesterol and apolipoprotein A-I together with a decrease in cholesterol ester transfer protein activity, and to induce hepatic cholesterol 7α-hydroxylase and cholesterol and bile acid elimination from the body. By raising the activities of apolipoprotein A-I/ high density lipoprotein-associated paraoxonase and other antioxidative enzymes, the inducers have the capacity to prevent atherogenesis in arterial walls through inhibition of the oxidative modification of low density lipoprotein. Other antiatherogenic vascular actions of high density lipoprotein include interference with low density lipoprotein aggregation and uptake by endothelial cells, and competition with low density lipoprotein for endothelial-localized low density lipoprotein receptors. Apolipoprotein A-I/high density lipoprotein beneficially enhances fibrinolysis, decreases platelet aggregation, increases prostacyclin production and stabilization and prevents atherogenic immune and inflammatory responses. This gene activation or microsomal induction can prevent atherosclerosis and is a basis for tailoring effective new agents and optimal non-invasive therapy against atherosclerotic vascular disease, to promote health and enhance longevity.     

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin.

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.     

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease

Summary A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250 mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.     

Hypocholesterolaemic effects of an ethanol precipitate of Kabosu juice in stroke-prone spontaneously hypertensive rats fed a cholesterol-free diet

1. We have previously identified strong inhibitory effects of Kabosu (Citrus sphaerocarpa Hort.) juice precipitate (KJP) on cholesterol elevation in stroke-prone spontaneously hypertensive rats (SHRSP) fed a cholesterol diet. In the present study, to elucidate the hypocholesterolaemic mechanism, we examined the effect of dietary KJP on lipid metabolism by using SHRSP fed a cholesterol-free diet. 2. Compositions of the experimental diet containing 10% KJP powder were adjusted to those of the control diet. Seven-week-old male SHRSP were fed control or experimental diet for 2 weeks with free access to the diet and water. 3. Serum levels of cholesterol, phospholipid and triglyceride of the KJP group were significantly reduced, which was due to decreases in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions. 4. Serum concentrations of apolipoproteins A-I and E (apoA-I and E) of the KJP group were significantly lower than those of the control group, whereas no significant differences were observed in serum apoB and apoA-IV between the two groups. 5. In liver, there were no significant differences in the contents of lipids or relative liver weight between the two groups. The activity of microsomal cholesterol 7alpha-hydroxylase of the KJP group tended to increase, whereas that of microsomal acyl-coenzyme A : cholesterol acyltransferase was significantly reduced, compared with the control group. 6. These results indicate that dietary KJP produces reductions of serum lipid levels, which are due to reductions in VLDL, apoE HDL and apoA-I HDL, and may promote catabolism and excretion of hepatic cholesterol in SHRSP fed a cholesterol-free diet.     

Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled type 2 diabetes mellitus

This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease.     

急性脑梗死患者血脂和载脂蛋白A1、B水平变化的探讨

目的探讨血脂和载脂蛋白A1、B与急性脑梗死的关系。方法选择160例急性脑梗死（ACI）患者,测定血清中总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）及载脂蛋白A1（apoA1）和载载脂蛋白B（apoB）水平的变化,与对照组进行比较 并对病情的严重程度与血脂水平的关系进行探讨。结果急性脑梗死组患者血清TG、TC和LDL-C均比对照组显著为高（P〈0.05或P〈0.01）,但HDL-C、apoB水平较对照组显著降低（P〈0.01和0.05）。中、重型组的TG、TC、HDL-C、LDL-C、apoB和重型apoA、水平与轻度组相比,差异均有极显著性（P〈0.01或0.05） 与中型组相比,重型组的TG、TC、HDL-C、apoB水平均有显著性变化（P〈0.05或0.01）,但LDL-C、apoA无显著性变化。结论血脂和与载脂蛋白A1、B水平与急性脑梗死的发病和病情及预后有密切的关系。     

Enzyme induction and renal function in man.

1. In a previous study in rats, an increased PAH clearance was found following chronic phenobarbitone administration. These results formed the basis for the present study in which fifteen healthy male volunteers were investigated and the parameters of liver microsomal enzyme activity and renal function were measured. 2. As parameters of liver microsomal enzyme activity, the antipyrine elimination in the plasma, the gamma-glutamyl-transpeptidase and the D-glucaric excretion in the urine were measured. Endogenous creatinine clearance, 51Cr-EDTA and 125I-Hippuran clearance were determined as measurements of renal function. 3. No correlation was found between any of the parameters of microsomal enzyme activity and renal function. 4. Of the fifteen volunteers, seven having a mean antipyrine half-life of 13.3 h were given antipyrine (500 mg) daily for 3 weeks. Afterwards all measurements of liver microsomal enzyme activity and renal function were repeated. The antipyrine half-life decreased to 8.5 h, while the antipyrine clearance was increased by about 56%. gamma-glutamyl-transpeptidase and D-glucaric acid were also significantly increased, while renal function remained unchanged. 5. Therefore, an increased PAH-clearance, as found in the rat, is not obtained in man following induction of liver microsomal enzyme activity.     

阿立哌唑对精神分裂症患者催乳素及糖脂水平影响的临床研究

目的探讨精神分裂症患者服用阿立哌唑治疗前后催乳素（PRL）及糖脂水平的变化。方法60例精神分裂症患者接受阿立哌唑治疗8周。于治疗前和治疗4,8周抽取空腹血,测定PRL、血糖（GLU）、甘油三脂（TG）、总胆固醇（T—CH）、高密度脂蛋白胆固醇（HDL-c）、载脂蛋白AL（apoA1）、载脂蛋白B（apoB）水平。结果治疗4周和8周,男、女患者PRL水平均较治疗前有所下降,但差异无显著性意义（P均〉0．05）,比较治疗前和治疗4周、8周后GLU、TG、T－CH、HDL—c、ApoAI、ApoB水平。差异均无显著性意义（P均〉0．05）。结论阿立哌唑对精神分裂症患者的PRL和糖脂水平无明显影响。     

酚噻嗪类药物对精神分裂症患者血清载脂蛋白、脂蛋白含量的影响

目的:探讨长时间(1月-25年)接受酚噻嗪类药物治疗后的精神分裂症患者引起血脂代谢紊乱的危险因素及其临床意义。方法:采用酶法、免疫透射比浊法检测了120例慢性精神分裂症患者、50例血管性痴呆患者和100例健康体检者血总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白AI(ApoAl)、载脂蛋白B(ApoB)的水平.结果:精神分裂症、血管性痴呆患者血ApoAI,HDL-C,ApoAI/ApoB含量明显低于健康对照组(P<0.01),ApoB、TG水平分别显著高于健康对照组(P<0.01),其中阴性症状组和血管性痴呆组TG含量明显高于阳性症状组(P<0.01),而三组病人TC的水平与正常对照组相比差异无显著性(P>0.05)。结论:长时间服用酚噻嗪类药物治疗后的慢性精神分裂症患者存在着血脂代谢紊乱,应在治疗精神分裂症的同时服用降脂、降粘、扩血管等药物,以预防和降低诱发心、脑血管病的危险因素,并达到延缓和推迟患者智能障碍以及痴呆的发展。     

Effect of tacrine hydrochloride on hepatic drug metabolism.

The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%, respectively (P<0.001). NORA was identifiable when antipyrine was incubated with NADPH alone, but could not be identified after incubation with either cimetidine or THA. This study has shown that THA causes the inhibition of AP metabolism to HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different hepatic microsomal cytochrome P-450 enzyme sub-families.     

Regulation of hepatic cholesterol metabolism in CETP/LDLr mice by cholesterol feeding and by drugs (cholestyramine and lovastatin) that lower plasma cholesterol

1. The hepatic mechanisms involved in the simultaneous regulation of plasma cholesterol concentration and cholesteryl ester transfer protein (CETP) activity were investigated by sharply modifying the hepatic rates of cholesterol synthesis. This was accomplished by cholestyramine, lovastatin and cholesterol feeding in human CETP transgenic mice cross-bred with low-density lipoprotein receptor (LDLr)-knockout mice, generating CETP(+/-)/LDLr(+/-) mice, which present a plasma lipoprotein profile resembling that of humans. 2. Analyses of pooled data showed that the plasma CETP activity correlated positively with plasma total cholesterol concentration, hepatic CETP mRNA and the liver microsomal cholesterol content; a negative correlation was found between plasma CETP activity and the liver 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and LDLr mRNA levels. These coordinated events represent an efficient control system that stabilizes the cell cholesterol content. 3. Nonetheless, not all cholesterol metabolism regulatory systems seem to fit into a coherent pattern of responses, suggesting that other unknown cellular mechanisms play roles depending on the type of pharmacological intervention. 4. For example, microsomal cholesterol content was not affected by cholestyramine, but was increased on cholesterol feeding (as predicted), and, surprisingly, on lovastatin treatment. Furthermore, although both plasma cholesterol-lowering drugs increased CYP7A1 mRNA and had no effect on CYP27 mRNA, other metabolic components were differentially modified. Cholestyramine and lovastatin, respectively, did not modify and increased both HMG-CoA and sterol responsive element binding protein 1c mRNA, did not modify and lowered liver X receptor alpha mRNA, lowered and increased ATP binding cassette A1 mRNA and lowered and did not modify scavenger receptor B1 mRNA. 5. That is, different to unabsorbed cholestyramine, lovastatin, as an absorbed plasma cholesterol-lowering drug, may have modified the activity of other unknown genes that play roles in the interaction of CETP with the metabolism of hepatic cholesterol.     

The effect of enzyme induction on diazepam metabolism in man.

1 The elimination and metabolism of diazepam in man was investigated following the induction of the liver microsomal enzyme system by antipyrine. 2 Seven healthy volunteers were given 1200 mg antipyrine as an inducing agent for a period of 14 days. Before and after the induction period the elimination of diazepam and desmethyldiazepam was measured in the plasma by gaschromatography. As parameters of liver microsomal enzyme activity, antipyrine elimination and gamma-glutamyl-transpeptidase in the plasma, D-glucaric acid and 6-beta-hydroxycortisol urinary excretion were measured on both occasions. 3 Following the induction period most parameters of microsomal enzyme activity measured were significantly changed indicating an increase of the microsomal enzyme system. The elimination of diazepam was significantly altered having a half-life of 37 h before and 18 h afterwards combined with a significant increase in total body clearance after the induction period, although the volume of distribution remained unaltered. The formation of the main metabolite N-desmethyldiazepam was not changed, but its elimination was increased having a half-life of 139 or 58 h respectively. 4 The elimination of unchanged diazepam and desmethyldiazepam is significantly increased by the induction of the liver microsomal enzyme system using antipyrine as an inducing agent in healthy volunteers, which might be important under certain clinical conditions.