The role of the liver in drug metabolism
TL;DR: An overload of the liver cell with numerous lipid- soluble drugs increases drug metabolizing enzymes in the endoplasmic reticulum and augments the smooth membranes in the hepatocytes with the results that all lipid-soluble compounds reacting with cytochrome-P450 are oxidized more rapidly.
About: This article is published in The American Journal of Medicine.The article was published on 1970-11-01. It has received 211 citations till now. The article focuses on the topics: Endoplasmic reticulum & Liver cell.
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TL;DR: Ethane evolution in vivo was stimulated by prior administration of phenobarbital and it was diminished by prior injection of α-tocopherol, suggesting that ethane production may be a useful index of lipid peroxidation in tissue homogenates and in intact animals.
Abstract: Homogenates of mouse liver and brain at 37 degrees C spontaneously formed lipid peroxides and simultaneously evolved ethane. alpha-Tocopherol, a lipid antioxidant, blocked ethane formation. When mice were injected with carbon tetrachloride (a liquid prooxidant for liver), the animals produced ethane. Ethane evolution in vivo was stimulated by prior administration of phenobarbital and it was diminished by prior injection of alpha-tocopherol. These data suggest that ethane production may be a useful index of lipid peroxidation in tissue homogenates and in intact animals.
420 citations
TL;DR: The goal is to discuss the current and emerging applications of 3D printing in medicine, a brief summary on additive manufacturing technologies and available printable materials, and the technological and regulatory barriers that are slowing down the full implementation of 3d printing in the medical field.
Abstract: Three-dimensional (3D) printing enables the production of anatomically matched and patient-specific devices and constructs with high tunability and complexity. It also allows on-demand fabrication with high productivity in a cost-effective manner. As a result, 3D printing has become a leading manufacturing technique in healthcare and medicine for a wide range of applications including dentistry, tissue engineering and regenerative medicine, engineered tissue models, medical devices, anatomical models and drug formulation. Today, 3D printing is widely adopted by the healthcare industry and academia. It provides commercially available medical products and a platform for emerging research areas including tissue and organ printing. In this review, our goal is to discuss the current and emerging applications of 3D printing in medicine. A brief summary on additive manufacturing technologies and available printable materials is also given. The technological and regulatory barriers that are slowing down the full implementation of 3D printing in the medical field are also discussed.
355 citations
TL;DR: It is not possible at present to give a clear answer to the question of whether bile salts participate in the initiation or perpetuation of human liver disease, although the evidence reviewed here suggests that in certain circumstances they may.
Abstract: Bile salts have deleterious effects on a variety of organs, cells, and subcellular organelles. Several bile salts, predominantly monohydroxy bile salts, have the capacity to produce cholestasis and changes in gross liver structure and hepatocytic ultrastructure in experimental animals and in vitro preparations. It is also apparent that liver disease results in profound changes in the pattern of bile acid metabolism, some of which theoretically could be harmful and some protective. It is not possible at present to give a clear answer to the question of whether bile salts participate in the initiation or perpetuation of human liver disease, although the evidence reviewed here suggests that in certain circumstances they may.
254 citations
TL;DR: It is suggested that lithocholic acid induces its own detoxification by activating nuclear receptors to promote transcription of genes encoding sulfotransferase, and work with CaCoi2 cells suggest that lithcholic acid may undergo sulfation in the enterocyte and be effluxed back into the intestinal lumen.
Abstract: Lithocholic acid, a monohydroxy, secondary bile acid, is formed by bacterial 7-dehydroxylation of the primary bile acid chenodeoxycholic acid (CDCA) and of the secondary bile acid ursodeoxycholic acid (UDCA). Lithocholic acid and its precursor CDCA are toxic when fed to the rabbit, rhesus monkey, and baboon, but not when CDCA, as well as UDCA, is used for therapeutic purposes in man. Older studies showed that the species specific toxicity of lithocholic acid could be explained by efficient sulfation of lithocholic acid in man and in chimpanzee, but not in the rabbit, rhesus monkey, or baboon. Rodents detoxify lithocholic acid by hydroxylation, but this does not occur in species in which it is toxic. Recent studies suggest that lithocholic acid induces its own detoxification by activating nuclear receptors to promote transcription of genes encoding sulfotransferase. In addition, work with CaCo2 cells suggest that lithocholic acid may undergo sulfation in the enterocyte and be effluxed back into the intestinal lumen. The evolution of trihydroxy bile acids in vertebrates may have occurred to decrease the formation of lithocholic acid. Lithocholic acid is a rare example of a toxic endobiotic; a variety of mechanisms have evolved to solve the problem of efficient detoxification.
237 citations
Cites background from "The role of the liver in drug metab..."
...He recognized that although such phase I biotransformations usually change a toxic xenobiotic to a non-toxic metabolite, they could as well transform a non-toxic compound to a toxic derivative (Remmer, 1970)....
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...Remmer speculated that the very cytochrome P450 enzymes that mediate drug hydroxylation were also involved in bile acid biosynthesis (Remmer, 1970)....
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TL;DR: The data suggest that the aminopyrine breath test is a safe, simple, qualitative and quantitative liver function test.
Abstract: The rate of hepatic metabolism of dimethylaminoantipyrine (aminopyrine), which occurs primarily through N-demethylation, was assessed by measurement of the specific activity of14CO2excrete...
221 citations
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Journal Article•
TL;DR: It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for thetreatment of Cushing's syndrome.
Abstract: In increasingly large numbers, drugs, pesticides, herbicides, food additives, and environmental carcinogenic hydrocarbons are being found to stimulate their own metabolism or the metabolism of other compounds. The evidence suggests that foreign chemicals exert this action by increasing the amount of drug-metabolizing enzymes in liver microsomes.Treatment of animals or man with suitable inducers of liver microsomal enzymes accelerates drug metabolism in vivo and alters the duration and intensity of drug action. For instance, barbiturates decrease the anticoagulant activity of coumarin anticoagulants by accelerating their metabolism. This effect requires that the dosage of coumarins be raised to obtain an adequate anticoagulant response, and serious toxicity can result after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose.
The stimulatory effect of drugs on their own metabolism often allows the organism to detoxify drugs more rapidly. This effect has considerable importance when it causes drugs to become less toxic and less effective during prolonged administration. However, if a metabolite has more activity than the parent drug, enzyme induction can enhance the drug's action. Enzyme induction may also be important during chronic exposure to environmental carcinogens, such as 3, 4-benzpyrene. The ability of 3, 4-benzpyrene to stimulate its own metabolism in liver, lung, gastrointestinal tract and skin represents an important mechanism for the detoxification of this substance.
Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes. Accordingly, treatment of rats with phenobarbital enhances the hydroxylation of androgens, estrogens, glucocorticoids, and progestational steroids by liver microsomes. This effect is paralleled in vivo by enhanced metabolism of steroids to polar metabolites and by a decreased action of steroids such as estradiol, estrone, and progesterone.
Recent studies suggest that inducers of liver microsomal enzymes enhance the hydroxylation of steroids in man. Phenobarbital, diphenylhydantoin, and phenylbutazone are examples of drugs that stimulate cortisol hydroxylase activity in guinea pig liver microsomes and enhance the urinary excretion of 6 β-hydroxycortisol in man. Further research is needed to learn whether the stimulatory action of drugs on the metabolism of normal body constituents is harmful or whether it restores a homeostasis that was upset by drug administration. It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for the treatment of Cushing's syndrome. Considerable further work is required to evaluate more completely the effects of liver microsomal enzyme inducers on the metabolism of bilirubin, cortisol, and other normal body constituents in experimental animals and man.
2,869 citations
Journal Article•
TL;DR: Two types of spectral changes are described as resulting from substrate interaction with a hepatic microsomal cytochrome; the magnitude of these spectral changes is dependent on protein concentration and substrate concentration as well as the substrate employed.
Abstract: Two types of spectral changes are described as resulting from substrate interaction with a hepatic microsomal cytochrome; the magnitude of these spectral changes is dependent on protein concentration and substrate concentration as well as the substrate employed. In two of the three types of substrates examined, the concentration of substrate necessary to evoke half-maximal enzyme activity was similar to the concentration of the same substrate necessary for half-maximal spectral changes. The addition of NADPH, a corequirement for the microsomal mixed function oxidase, causes a modification of both types of spectral changes, without altering substrate affinity. Three possible hypotheses are advanced, based upon the experimental observations, to explain the two types of spectral changes observed.
1,110 citations
Journal Article•
TL;DR: The knowledge that hepatic triglyceride secretion involves a dual mechanism has provided a powerful new guide for the analysis of mechanisms underlying fatty liver disease, and a central requirement of this hypothesis must be that if over supply of fatty acids is to be invoked as a significant factor in the pathogenesis of fatty liver, then the oversupply must be of sufficient magnitude and duration.
Abstract: During the past 20 years, study of the fatty liver induced by carbon tetrachloride has passed through 2 periods of revolutionary change, and at the present time a third revolutionary change is taking place. The dominant notion guiding most of the thinking before 1948 was that toxic and nutritional fatty liver disease could be understood in terms of failure in transport of fatty acids as phospholipids. As quantitative analyses of whole body phospholipid and neutral lipid metabolism became available through application of radioisotope technology, it became possible by 1953 to conclude that fatty acids were not transported in the plasma as phospholipids.
For the next 6 years work in this field was dominated by the mitochondrial hypothesis. Carbon tetrachloride was thought to damage the liver cell mitochondria. It was suggested that lipid accumulation was due to a failure of normal pathways of lipid oxidation, and that death of the liver cells resulted from interruption in energy-transducing mechanisms. By 1959 this hypothesis also proved untenable since accumulation of triglycerides and degeneration of the hepatocellular endoplasmic reticulum preceeded mitochondrial degeneration by many hours. The major contribution of the work of this period was the introduction into the study of experimental hepatic toxicology of methods of biochemical cytology.
A second revolutionary change took place in 1960. It became evident that carbon tetrachloride poisoning leads rapidly to cessation of movement of large quantities of triglycerides from the liver to the plasma. The blockade of hepatic triglyceride secretion by carbon tetrachloride accounts for the characteristic fatty liver. Earlier studies of rates of replacement of the different moieties of the plasma lipoproteins had demonstrated that low-density lipoprotein triglycerides were replaced much faster than the protein moiety. This work, as well as more recent studies combining use of the isolated, perfused liver with methods for separation of plasma protein and lipoprotein fractions, has made possible a most important new insight into the nature of hepatic triglyceride secretion. The latter can best be understood as a dual mechanism. One part of the mechanism involves hepatic biosynthesis of the various moieties of plasma low-density lipoproteins, coupling of these to form definitive lipoprotein molecules, and their extrusion to the plasma compartment. An auxiliary mechanism provides for re-entry into the system of triglyceride-free lipoprotein apoprotein. Movement of triglycerides from liver to plasma depends largely on the continuous functioning of the second, or auxiliary arm of the cycle. The knowledge that hepatic triglyceride secretion involves a dual mechanism has provided a powerful new guide for the analysis of mechanisms underlying fatty liver disease. In the case of carbon tetrachloride poisoning, the rapid onset of liver triglyceride accumulation most probably results mainly from cessation in function of the auxiliary coupling phase of hepatic triglyceride secretion, and less significantly from a breakdown in hepatic protein synthesis.
During this period, ca . 1960 to 1965, highly provocative experimental findings led to an attempt to rationalize the hepatocellular necrosis and the triglyceride accumulation of carbon tetrachloride poisoning in terms of massive discharge of the sympathetic nervous system. The main evidence regarding the pathogenesis of hepatocellular necrosis was based on the observation that rats whose spinal cord had been divided were remarkably immune to the toxic agent. A review of the evidence does not support the contention that hepatocellular necrosis is a consequence of catecholamine discharge.
The catecholamine hypothesis suggested that hepatic lipid accumulation is due to an oversupply of fatty acids mobilized from peripheral adipose tissue depots. Activation of the hypophyseal-adrenocortical axis has also been invoked in support of the peripheral oversupply hypothesis. A central requirement of this hypothesis must be that if oversupply of fatty acids is to be invoked as a significant factor in the pathogenesis of fatty liver, then the oversupply must be of sufficient magnitude and duration to account for the time course of the hepatic lipid accumulation. From this point of view the evidence offered in support of the peripheral oversupply hypothesis is not convincing. In particular, for carbon tetrachloride poisoning, at a time when liver triglycerides are increasing rapidly, there is no increase in flux of fatty acids through the plasma compartment.
The most recent work in this field has inaugurated a third revolution in the study of carbon tetrachloride hepatotoxicity. Its essential feature is the recognition that carbon tetrachloride toxicity depends on cleavage of the carbon-tochlorine bond. At the same time, the long-held view that the toxic action of carbon tetrachloride resided in its effectiveness as a lipid solvent has finally been discarded. An important link has been established between the metabolism of carbon tetrachloride and the peroxidative decomposition of cytoplasmic membrane structural lipids. Sufficient data are not yet available to decide whether the latter effect is a major or minor consequence of the metabolism of carbon tetrachloride. The important point is that study of this problem has reached the organic chemical level of organization. This augurs well for the immediate future, which should witness further interesting new developments in the study of haloalkane toxicity.
918 citations
Journal Article•
TL;DR: Although liver microsomes from male rats metabolize most drugs more rapidly than do those from female rats, the magnitude of the sex difference varies markedly with the substrate and the effects of starvation of male rats range from impairment of sex-dependent enzymes which metabolize aminopyrine and hexobarbital to enhancement of thesex-independent enzyme that hydroxylates aniline.
Abstract: Although liver microsomes from male rats metabolize most drugs more rapidly than do those from female rats, the magnitude of the sex difference varies markedly with the substrate. There is more than a 3-fold sex difference with substrates like aminopyrine and hexobarbital, but virtually no sex difference in the hydroxylation of aniline and zoxazolamine. The effects of starvation of male rats range from impairment of sex-dependent enzymes which metabolize aminopyrine and hexobarbital to enhancement of the sex-independent enzyme that hydroxylates aniline. In contrast, starvation of female rats increases the specific activity of the aminopyrine- and hexobarbital-metabolizing enzymes as well as aniline hydroxylase. Since the sex-dependent enzymes are impaired in fasted male rats but enhanced in fasted female rats, starvation diminishes if it does not abolish the sex difference in the metabolism of drugs by rat liver microsomes. Starvation does not alter the metabolism of hexobarbital and enhances the metabolism of aminopyrine by liver microsomes from castrated rats, but impairs the metabolism of these compounds by liver microsomes from castrated rats receiving methyltestosterone.
543 citations
462 citations