Factors influencing induction of hepatic microsomal drug-metabolizing enzymes

Kato, Ryuichi; Chiesara, E.; Vassanelli, P

doi:10.1016/0006-2952(62)90076-x

Cited by 103 publications

(22 citation statements)

References 8 publications

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“…3. Activities of NADPH oxidase, NADPH-cytochrome c reductase and NADPH neotetrazolium diaphorase and amounts of cytochrome b5 and P-450 in male and female rats bearing Walker 256 carcinosarcoma Since the alternations in the activities of drug-metabolizing enzymes were often relat ed to the alternations in the activities of NADPH-dependent electron transport system of liver microsomes (5,12,16,(32)(33)(34)(35)(36), the activities of NADPH oxidase , NADPH-cytochrome c reductase and NADPH-neotetrazolium diaphorase and the amounts of cytochrome b5 and P-450 in the male and female rats bearing Walker 256 carcinosarcoma were investigated .…”

Section: Fig 1 Activities Of Pentobarbital Oxidase Carisoprodol Oxmentioning

confidence: 99%

“…This fact is, especially, important for some drugs which should be converted to the active metabolite in vivo (5-7). Some carcinogenic and carcinostatic compounds, such as dimethylnitrosamine, 2-acethylaminofluorene, 4-nitroquinoline N oxide and cyclophosphoramide, belong to this group (8-11).The activities of drug-metabolizing enzymes of liver microsomes are markedly altered by several factors, such as, the administrations of different kind of lipid soluble compounds and anabolic hormones, starvation, low protein diet, formaline and adrenaline stress, al loxan diabetes, hyperthyroidism, adrenalectomy, viral hepatitis and hepatectomy (1,3,(12)(13)(14)(15)(16)(17)(18)(19)(20).In a preliminary work,* we observed a decrease in the metabolism of pentobarbital, meprobamate and strychnine in Walker 256 carcinosarcoma bearing male rats. How ever, there are clear sex difference in the alternation of activities of drug-metabolizing enzymes by the non-physiological conditions.…”

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confidence: 99%

“…The activities of drug-metabolizing enzymes of liver microsomes are markedly altered by several factors, such as, the administrations of different kind of lipid soluble compounds and anabolic hormones, starvation, low protein diet, formaline and adrenaline stress, al loxan diabetes, hyperthyroidism, adrenalectomy, viral hepatitis and hepatectomy (1,3,(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

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Drug Metabolism in Tumor-Bearlng Rats

Kato

Takanaka

Takahashi

et al. 1968

Japanese Journal of Pharmacology

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It has recently been recognized that the metabolism of lipid soluble compounds by liver microsomal enzymes is highly important factors for controlling the action and toxicity of various drugs (1-5). This fact is, especially, important for some drugs which should be converted to the active metabolite in vivo (5-7). Some carcinogenic and carcinostatic compounds, such as dimethylnitrosamine, 2-acethylaminofluorene, 4-nitroquinoline N oxide and cyclophosphoramide, belong to this group (8-11).The activities of drug-metabolizing enzymes of liver microsomes are markedly altered by several factors, such as, the administrations of different kind of lipid soluble compounds and anabolic hormones, starvation, low protein diet, formaline and adrenaline stress, al loxan diabetes, hyperthyroidism, adrenalectomy, viral hepatitis and hepatectomy (1,3,(12)(13)(14)(15)(16)(17)(18)(19)(20).In a preliminary work,* we observed a decrease in the metabolism of pentobarbital, meprobamate and strychnine in Walker 256 carcinosarcoma bearing male rats. How ever, there are clear sex difference in the alternation of activities of drug-metabolizing enzymes by the non-physiological conditions. For example, starvation, formalin and ad renaline stress, alloxan diabetes, hyperthyroidism and adrenalectomy markedly decrease the activities of most of the enzymes in male rats, while they did not significantly alter or rather increased the activities in female rats (13,14).It would be, thus, interesting to investigate whether the decrease in the metabolism of drugs by liver microsomes of the tumor-bearing rats is only limited to male rats. Moreover, whether the activities of other drug-oxidizing enzymes, drug-reducing enzymes and electron transport systems is affected or not by tumor-bearing was investigated.Furthermore, in order to obtain some insights in the mechanism of decrease in the activities of drug-metabolizing enzymes in tumor-bearing rats, the effect of phenobarbital treatment on these enzyme activities in control rats and tumor-bearing rats was compara tively investigated.

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Section: Fig 1 Activities Of Pentobarbital Oxidase Carisoprodol Oxmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Drug Metabolism in Tumor-Bearlng Rats

Kato

Takanaka

Takahashi

et al. 1968

Japanese Journal of Pharmacology

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“…Animal experiments have demonstrated impaired metabolism of several barbiturates after various forms of liver damage. Carbon tetrachloride administration (Kato, Chiesara & Vassanelli, 1962), partial hepatectomy (Masson & Beland, 1945), obstructive jaundice (McLuen & Fouts, 1961) and viral hepatitis (Kato, Nakamura & Chiesara, 1963) all reduce barbiturate metabolism in laboratory studies.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of amylobarbitone in patients with chronic liver disease

Mawer

Miller

Turnberg

1972

British J Pharmacology

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Summary A single dose of amylobarbitone (3·23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured. The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3·5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3·5 g/100 ml). The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system. The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant β(h−1) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0·01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0·001) and the mean serum water clearance (Ce ml/min) representing amylobarbitone elimination by metabolism was reduced. The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism. Both patient groups showed an increase in the first dispositional rate constant α(h−1) and in the clearance (Ct ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain. The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0·11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.

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“…The activities of drug metabolizing enzymes were altered by several factors, such as administration of some drugs, anabolic hormone, alloxan diabetes, hyperthyroidism and starvation (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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Effect of Starvation on the in Vivo Metabolism and Effect of Drugs in Female and Male Rats

Kato

Takanaka

1967

Jpn.J.Pharmacol

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The enzymes which metabolize lipid soluble compounds are localized in microsomes of liver and reduced NADP and molecular oxygen are required as cofactors. It was recently demonstrated that the activities of drug-metabolizing enzymes are an important factor for controling the action and toxicity of drugs (1-9).The activities of drug metabolizing enzymes were altered by several factors, such as administration of some drugs, anabolic hormone, alloxan diabetes, hyperthyroidism and starvation (1-15).1 n previous papers, it was reported that the activity of drug-metabolizing enzymes of liver microsomes in male rats was markedly decreased by starvation, while the activity i n female rats was increased (14).The starvation caused a decrease in liver weight as well as body weight and the blood flow of liver. On the other hand, studies on electron microscopy showed that endoplasmic reticulum in liver of fasted rats was markedly altered in their fine structure by starvation (16,17). Moreover, it has been considered that microsomes are artifacts during the homo genization of liver and they are likely derived from the endoplasmic reticulum. Thus, there is a possibility that the alternations in the enzyme activities in female and male rats may be artifacts during the homogenization.The purpose of the present investigation is to establish the correlation between the in vivo metabolism and activity of drugs and the in vitro metabolism of drugs in fasted female and male rats. METHODSFemale and male rats of \Vistar strain, weighing about 160 g and 180 g, respectively, were used. The rats were fasted for 2 days before the experiments.The estimation of drug ejects: The durations of pentobarbital narcosis, hexobarbital narcosis and zoxazolamine paralysis were measured by the duration of loss of righting reflex. Strychnine toxicity was determined by the percentage of convulsion and mortality. Toxi city of OMPA (Octamethylpyrophosphoramide) was determined by the median time of the onset of symptom, convulsion and death.

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Factors influencing induction of hepatic microsomal drug-metabolizing enzymes

Cited by 103 publications

References 8 publications

Drug Metabolism in Tumor-Bearlng Rats

Drug Metabolism in Tumor-Bearlng Rats

Metabolism of amylobarbitone in patients with chronic liver disease

Effect of Starvation on the in Vivo Metabolism and Effect of Drugs in Female and Male Rats

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