Effects of phthalic acid esters on drug metabolizing enzymes of rat liver

Di(2-ethylhexyl)phthalate (DEHP) inhibited UDP-glucuronyltransferase activity of rat liver in vitro and in vivo. Diethyl phthalate and dimethoxyethyl phthalate also inhibited this enzyme in vitro. On the other hand, DEHP did not inhibit the activity of the cytosolic enzyme N-acetyltransferase; it also did not alter the levels of rat liver microsomal cytochrome P-450 in vitro. It is suggested that DEHP may alter the composition of microsomal phospholipids.     

Induction of rat hepatic drug metabolizing enzymes by substituted urea herbicides

Effects of eight structurally closely related substituted urea herbicides were investigated on the induction of cytochrome P-450 dependent monooxygenase enzyme complex, as well as on two conjugating enzymes after short-term treatment of rats. Liver microsomal cytochrome P-450 content was induced approximately by 50%. Cytochrome P-450 dependent monooxygenase activities showed a great variety depending on the substrate and on the herbicide. Two-18-fold induction was detected with 7-ethoxycoumarin, while up to 8-fold induction was measured with benzo(a)pyrene. Aldrin epoxidase activities were increased up to 3-fold, and aminopyrine N-demethylase activities were only slightly different from the control level. UDP-glucuronyltransferase and glutathione S-transferase activities were enhanced up to 2-fold. The results indicate that chemical structure of the related substituted urea compounds, the number of halogen substituents on their phenyl group exert a strong influence on the induction of monooxygenases.     

Effects of trans-sobrerol on drug metabolizing enzymes in the rat

1. Metabolism of 14C-trans-sobrerol (I) by Sprague-Dawley rat liver microsomes did not result in covalent binding to proteins, lipid peroxidation or cytochrome P-450 destruction. 2. Subacute and chronic treatment of Sprague-Dawley rats with (I) resulted only in an increase in liver cytosolic GSH-S-transferase. 3. Acute treatment of rats with trans-sobrerol or its metabolite, 8-hydroxycarvotanacetone (II) produced considerable GSH depletion, faster in the case of II, in both liver and lung; the original GSH levels were restored within 24 h. No significant increase in lipid peroxidation was found even when GSH was at its lowest level. 4. UDP-glucuronyltransferase and GSH-S-transferase conjugation occurred with trans-sobrerol and some of its metabolites although at low rates.     

外源性一氧化氮对大鼠肝脏抗氧化物酶和药物代谢酶活性的影响

用亚硝基铁氰化钠(SNP)作为NO生成前体,以 0, 1, 2, 4 和 8 mg·kg^-1 ip 给予大鼠,每日一次,连续 5 d,来研究外源性NO对大鼠肝脏细胞色素 P450, 苯胺羟化酶(AH), 谷胱甘肽S-转移酶(GST)等药物代谢酶和过氧化氢酶(Cat), 谷胱甘肽过氧化物酶(GSH-Px), 超氧化物歧化酶(SOD)等抗氧化物酶活性以及脂质过氧化的体内影响情况. 结果表明外源性NO能明显降低大鼠肝脏SOD, Cat, AH 的活性和细胞色素P450的含量(P<0.05),并且高剂量组还能明显促进脂质过氧化发生(P<0.05), 但对GSH-Px和GST的活性则无明显影响.     

Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes

Gallic acid and its structurally related compounds are found widely distributed in fruits and plants. Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea. Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry. In addition, gallic acid is employed as a source material for inks, paints and colour developers. Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties. In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined. Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests. In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles. There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents. Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food. Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential. However, it must be noted that numerous constituents of foodstuffs have been found to be potent modulators of xenobiotic metabolism and the net human health effects may depend on concentrations of individual components and individual genetic makeup.     

外源性一氧化氮对大鼠肝脏抗氧化物酶和药物代谢酶活性的影响

用亚硝基铁氰化钠（ＳＮＰ）作为ＮＯ生成前体,以０,１,２,４和８ｍｇ·ｋｇ－１ｉｐ给予大鼠,每日一次,连续５ｄ,来研究外源性ＮＯ对大鼠肝脏细胞色素Ｐ４５０,苯胺羟化酶（ＡＨ）,谷胱甘肽Ｓ－转移酶（ＧＳＴ）等药物代谢酶和过氧化氢酶（Ｃａｔ）,谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）,超氧化物歧化酶（ＳＯＤ）等抗氧化物酶活性以及脂质过氧化的体内影响情况．结果表明外源性ＮＯ能明显降低大鼠肝脏ＳＯＤ,Ｃａｔ,ＡＨ的活性和细胞色素Ｐ４５０的含量（Ｐ＜０．０５）,并且高剂量组还能明显促进脂质过氧化发生（Ｐ＜０．０５）,但对ＧＳＨ－Ｐｘ和ＧＳＴ的活性则无明显影响     

Effects of methyl methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys

Male Wistar rats received methyl methacrylate monomer (MMA) i.p. in olive oil 1.0 g/kg body weight on 3 successive days. The weight of the livers and kidneys, and the body weights did not differ from their controls. On the fifth day after treatment, hepatic NADPH-cytochrome c reductase, 7-ethoxycoumarin 0-deethylase and the 2,5-diphenyloxazole hydroxylase exhibited maximal decreases in activity (25%, 58%, 36%, respectively) without any coincident effect on the total amount of cytochrome P-450 hemoprotein itself. One week later these activities had returned to control levels. The enzymatic changes in the kidneys were smaller in magnitude, and they were also reversed sooner. A single i.p. dose of MMA (2 g/kg body weight) caused elevation of serum alanine aminotransferase activity. A tenfold increase of the excretion rate of urinary thioethers was also discovered. The hepatic reduced glutathione (GSH) was depleted in 3 h to 20% and the GSSG to half of the value in controls. In kidneys, the GSH was decreased to 48% in 3 h before an apparent phase of overrecovery. At the end of the 24 h observation period, cytochrome P-450 concentrations were somewhat decreased in the liver. The GSH contents showed dose and time-dependent reversible decreases in isolated hepatocytes when incubated for 2 h in a medium containing MMA at the nominal concentrations of 0, 2, 5, or 10 mM. None of the treatments affected either the content of cytochrome P-450 or the viability of the liver cells.     

Determination of drug metabolizing enzymes in needle biopsies of human liver

Summary A micromethod is described for determination of the cytochrome P-450 content, demethylation rate of aminopyrine and p-nitroanisole, the activities of NADPH-cytochrome-c-reductase, pseudocholinesterase and glucose-6-phosphatase in homogenates of the small amount of human liver (about 20 mg) obtained by needle biopsy. 1 g of human liver contains 32–38 mg microsomal protein, much less than that present in rat liver (50–60 mg/g liver). The cytochrome P-450 content in normals was 10.8±2.6 nmoles/g liver wet weight (mean±1 S.D.). In severe hepatitis and cirrhosis the cytochrome P-450 content fell to 50% of the control value, whereas mild and moderate hepatitis did not produce any change. Similarly, only in seriously damaged livers were the demethylationrates of both substrates lowered. The activity of the NADPH-cytochrome-c-reductase was 1.88±0.51 micromoles/g liver × min and was not impaired even by severe liver damage. The activities of glucose-6-phosphatase and pseudocholinesterase also fell only in severe liver disease.     

Interactions between theophylline and drug metabolizing liver enzymes in the rat

Theophylline induces increase of hepatic cytochrome P-450 contents and P-450 dependent polysubstrate monooxygenases (e.g. p-nitroanisol-demethylase, 7-ethoxycoumarin-deethylase) in rats and other animals and in man. The purpose of this study is to investigate the long-term effect of theophylline on hepatic cytochrome P-450 and P-450 dependent enzyme activities in rats. P-450 content is enhanced after 6 days treatment with theophylline (150 mg/kg/d orally), but reaches the initial level after 28 days treatment. However, the P-450 dependent enzyme activities (7-ethoxycoumarin-deethylase, p-nitroanisol-demethylase) remain elevated. The in vitro inhibition of 7-ethoxycoumarin-deethylase by alpha-naphthoflavone and metyrapone suggests a mixed type induction by theophylline. Treatment of the animals with phenobarbital and theophylline or with benzo(alpha)pyrene and theophylline does not lead to an enhancement of P-450 content compared with a treatment solely by phenobarbital or benzo(alpha)pyrene. However, the simultaneous application of theophylline and phenobarbital increases the 7-ethoxycoumarin-deethylase and p-nitroanisol-demethylase activities compared with an exclusive phenobarbital treatment, whereas the benzo(alpha)pyrene effect is not enhanced by theophylline.     

药物代谢酶的分子遗传学

综述近１０年来国内外有关药物代谢酶的分子遗传学进展,介绍药物代谢酶的基本概念并重点探讨了具有遗传多态性的两种氧化酶（细胞色素Ｐ４５０酶ＣＹＰ２Ｄ６,ＣＹＰ２Ｃ１９）和一种结合酶（Ｎ 乙酰化转移酶）的个体和种族差异。最后主要讨论了表型分型和基因分型在药物代谢酶研究中的一些应用。     

The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes

Cirrhosis is the end stage of many forms of liver pathologies including hepatitis. The liver is known for its vital role in the processing of xenobiotics, including drugs and toxic compounds. Cirrhosis causes changes in the architecture of the liver leading to changes in blood flow, protein binding, and drug metabolizing enzymes. Drug metabolizing enzymes are primarily decreased due to loss of liver tissue. However, not all enzyme activities are reduced and some are only altered in specific cases. There is a great deal of discrepancy between various reports on cytochrome p450 alterations in liver cirrhosis, likely due to differences in disease severity and other underlying conditions. In general, however, CYP1A and CYP3A levels and related enzyme activities are usually reduced and CYP2C, CYP2A, and CYP2B are mostly unaltered. Both alcohol dehyrogenases and aldehyde dehydrogenases are altered in liver cirrhosis, although the etiology of the disease may determine the expression of alcohol dehydrogenases. Glucuronidation is mainly preserved, but there are a number of factors that determine whether glucuronidation is affected in patients with liver cirrhosis. Low sulphation rates are usually found in patients with liver disease but a decrease in sulfatase activity compensates for the decrease in sulphation rates. In all cases, a reduction in drug metabolizing enzyme activities in liver cirrhosis contributes to decreased clearance of drugs seen in patients with liver abnormalities. The reduction in drug metabolizing enzyme activity must be taken into consideration when adjusting doses, especially in patients with severe liver disease.     

Effect of toluidines on drug metabolizing enzymes in rat liver,kidney and lung

The effect of pretreatment with o-, m- and p-toluidine on the drug-metabolizing enzymes of liver, kidney and lung in rats were investigated. The activities of microsomal aryl hydrocarbon hydroxylase (AHH), amino-pyrine demethylase, NADPH-cytochrome c reductase, epoxide hydrolase, cytosolic glutathione S-transferase as well as the concentrations of cytochrome P-450 and cytochrome b₅ were determined. The obtained results showed that o-toluidine increased the activity of AHH in all tested organs; showed that o-toluidine increased the activity of AHH in all tested organs; a particularly marked increase was observed in the kidney. The activity of NADPH-cytochrome c reductase and the content of cytochrome b₅ were enhanced by o-toluidine only in the liver. m-Toluidine enhanced the glutathione S-transferase activity while the p-isomer increased both the epoxide hydrolase and the glutathione S-transferase activities. p-Toluidine decreased the AHH and aminopyrine demethylase activities and the cytochrome P-450 content. These results may explain in part the previously reported observations on carcinogenic activity of o-toluidine.     

Effects of benzodiazepines on enzymes metabolizing drugs. IV. Effect of diazepam and oxazepam on hepatic microsomal drug metabolizing enzymes in rats exposed to high environmental temperature

Administration of diazepam or oxazepam caused a different response of the rat hepatic microsomal cytochrome P-450 dependent monooxygenase system. Both drugs produced significant decrease in the activity of NADH: cytochrome c oxidoreductase in rats exposed to 21 degrees C, but not to 28 degrees C and 35 degrees C, and did not change the activity of aniline hydroxylase, aminopyrine N-demethylase and 4-nitroanisole O-demethylase and cytochrome b5 level at any tested temperatures. Oxazepam, but not diazepam, caused a decrease in cytochrome P-450 content in rats exposed to 21 degrees C only. The results indicate that the high ambient temperature modifies the effect of tested benzodiazepines on the activity of some microsomal enzymes.     

Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicides in rats

Male Wistar rats were treated daily by gavage with two phenoxy herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D)(100-200 mg/kg body wt) and 4-chloro-2-methylphenoxyacetic acid (MCPA) (100-200 mg/kg body wt), and with the chemically different glyphosate N-phosphonomethyl glycine (300 mg/kg body wt) 5 days per week for 2 weeks. A hypolipidemic drug, clofibrate [ethyl-2-(4-chlorophenoxy)-2-methylpropionate], which is structurally related to phenoxy acids, was used as a positive control (200 mg/kg body wt). 2,4-D and MCPA had several effects similar to those of clofibrate: all three compounds induced proliferation of hepatic peroxisomes, decreased serum lipid levels, and increased hepatic carnitine acetyltransferase and catalase activities. 2,4-D and MCPA, but not clofibrate, decreased lipoprotein lipase activity in the adipose tissue to about a third of the control value but did not change the lipoprotein lipase activity in the heart muscle. The data suggest that these compounds cause hypolipidemia not by enhancing the storage of peripheral lipids in adipose tissue but by preferentially increasing lipid utilization in the liver. Glyphosate caused no peroxisome proliferation or hypolipidemia, suggesting that these effects are associated with the structural similarity between phenoxy acid herbicides and clofibrate.     

Induction of drug metabolizing enzymes by sulfinpyrazone

Summary A previous interaction study of sulfinpyrazone (Anturano®) suggested that it induced microsomal drug metabolizing enzymes in the liver. To verify this finding the effect of sulfinpyrazone 800 mg per day for four weeks was investigated in ten healthy volunteers. Both the therapeutic actions of sulfinpyrazone, the uricosuric and the antiaggregating effects, were demonstrated (p<0.05). The influence on the microsomal drug metabolizing system in the liver was demonstrated by an increase in serum--glutamyl transpeptidase from 15.1 to 23.3 U/l (p>0.05), a significant increase in the urinary excretion of d-glucaric acid (29.6 to 77.9 µMol/24 h,p<0.05) and an increase in antipyrine clearance from 50.3 ml/min to 83.9 ml/min (p<0.05). The possibility of enhancement of drug metabolism during treatment with sulfinpyrazone in combination with other drugs should be kept in mind.