Showing papers in "Pharmacological Reviews in 1967"

Pharmacological implications of microsomal enzyme induction

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after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose.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.

Carbon tetrachloride hepatotoxicity

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.

Sympathetic regulation of metabolism

Abstract: This long and extremely detailed study attempts at giving a review of the metabolic regulatory function of the sympathetic nervous system. The metabolic effects of adrenaline and noradrenaline are considered as it regards lipid metabolism carbohydrate metabolism and protein metabolism. The study also presents a new hypothesis of the calorigenic effect of catecholamines and a new classification of receptors for the metabolic effects of adrenaline and noradrenaline. The study concludes with an examination of the role of the sympathetic nervous system in the regulation of metabolism and of the use of drugs that modify sympathetic activity.

Chlorpromazine and endocrine function

Abstract: This review surveys the influence of CPZ on pituitary activity. Analysis of the literature indicates that the tranquilizer affects pituitary activity only in amounts that exceed those necessary to induce psychodepressant effects in animal species. In these amounts CPZ appears to block the release of FSH and LH and to stimulate the release of prolactin. It inhibits the discharge of TSH and it stimulates the secretion of ACTH and growth hormone. In addition it seems to increase the release of MSH and ADH and it may block oxytocin-release. The influence of the phenothiazines on pituitary secretion depends on the amount of the drug given, the duration of the treatment and the circumstances, like environmental temperature, under which experiments are performed. The pituitary-gonadal axis of all pituitary functions seems to be most susceptible to the drug in animals and man. Clinically the most frequently observed endocrine dysfunction lies in the pituitary-gonadal axis since amenorrhea and galactorrhea are most commonly seen in female patients treated chronically with relatively high doses of the drug. The locus of action of the drug with respect to pituitary activity must be sought in the brain, but extremely high doses of CPZ may antagonize the effect of pituitary hormones or the influence of the target hormones on their respective target tissues. In the brain CPZ may facilitate or inhibit structures that are involved in the control of pituitary secretions. Mesencephalic limbic and rhinencephalic limbic structures as well as the hypothalamus, which are known to be affected by CPZ and which are known to be involved in pituitary activity, should be regarded as the site of action of CPZ. Some of the effects of CPZ on pituitary activity may be explained by its adrenergic blocking properties. This is based upon the concept that blockade of ovulation, stimulation of prolactin release, as well as MSH release induced by CPZ can be brought about also by depletion of catecholamines in the hypothalamus. The effect of CPZ and related drugs on pituitary activity is complicated by the manifold actions of the phenothiazines in the body. Profound metabolic influences, hemodynamic effects, and marked disturbances in thermoregulation may affect pituitary secretion in a nonspecific manner. These considerations make it difficult to analyze the site of the action of the drug. This can be overcome if better methods become available to determine pituitary activity. It may then be possible to re-evaluate the effect of the phenothiazines on endocrine activity. Only if direct measures to determine the respective pituitary hormones in the circulation are employed, and the effect of CPZ is assessed after a single injection or after chronic administration of the drug in various dosages and during various periods of time in animal and man under normothermic and hypothermic conditions, can the influence of CPZ and related drugs on endocrine activity be established with certainty.

Recent advances in chemotherapy of viral diseases

Abstract: Within recent years 2 compounds, idoxuridine (IUdR, 5-iodo-2'-deoxyuridine) and amantadine (Symmetrel), have been approved by the Food and Drug Administration for use in the treatment or prevention of disease caused by viruses in man. The explosive burst of interest in the biochemistry of the reproduction of both RNA and DNA viruses should provide the medicinal chemist with directions for the design of further compounds that have antiviral activity with favorable therapeutic indices. This optimistic hope should be realized within the next decade. The possible if not probable role of viruses in the induction of at least some neoplasms in man is an extremely important direction of present day activities in virology. The prevention of viral infections by vaccines offers great promise of being extended into those diseases at present not under control. However, even if prevention were achieved it would be advantageous to have drugs that could abort those viral infections that do develop. Although these conclusions may appear enthusiastic, they seem justified in view of the rapid developments being made in our understanding of the biochemistry of viruses and their interrelationship with the host cell on a molecular level.

Biochemical aspects of the actions of drugs on spermatogenesis

Abstract: Although it is perhaps still premature to attempt to assign the different reactivities of the numerous cytotoxic agents that have been tried in spermatogenesis to the different categories of damage they produce, as outlined in the introduction to this review, a tentative grouping may nevertheless be considered worthwhile, if only to be criticized and proven invalid by further work. Kinetic damage . This is difficult to recognize, since it requires a tedious examination of the distribution and proportion of the phases of the testis present in any transverse section of the tubule at different times after treatment with the drug. The only satisfactory demonstration of true kinetic damage is probably the observation of the changing pattern of mitoses observed after treatment of mice with 6-azauracil. From inadequate data, it may be inferred that this type of damage may be present after treatment with antiandrogens, bis(dichloroacetyl)diamines (WIN compounds), progestens, antimetabolites, dinitropyrrole, nitrofurans, thiophene derivatives, and cadmium salts and after elevation of testicular temperature. In none of these cases however has this type of damage been satisfactorily proven. Cellular damage . Its presence is more clearly defined, and most of the drugs examined, especially when the effects are noted by histological examination, have shown varying degrees of this form of damage. Spermatogonial damage has been observed with certain antiandrogens, although these cells may not be the most sensitive to these agents. Certain ethyleneimine derivatives, notably ethylene urea and ethylene urethane, show gross cell destruction in the testis. Of the alkane sulphonates, Busulphan, dimethyl busulphan, methylene dimethane sulphonate, and isopropyl methane sulphonate show spermatogonial damage. Methylhydrazine derivatives as well as cadmium salts also show gross damage to this cell type. Cellular damage to primary spermatocytes seems to be a characteristic feature of temperature elevation of the testis, and several drugs which are thought to be acting on the testis by inducing this mechanism, such as the dinitropyrrole, nitrofuran, thiophene, bis(dichloroacetyl)diamine derivatives as well as cadmium salts, also exert a major action on this cell type. Bis(dichloroacetyl)diamines also exert some action on spermatids at an early stage. The final proof of cellular damage is the quantitative measurement of the extent of pycnosis and fragmentation, but this is not often observed, either because of the rapid removal of damaged cells or owing to the failure of damaged cells to develop into the normal complement of more mature forms. Morphological damage . It is a point for discussion as to whether there should be a distinction between "cellular" and "morphological" damage, but if the cell survives for a period and leaves the testis with the spermatozoon, the damage is regarded as more persistent and classified as "morphological." Such changes in spermatid development have been noted after treatment with the alkane sulphonate derivatives, and have been described in detail in human studies after treatment with some of the bis(dichloroacetyl)diamines. Abnormal and bizarre forms of spermatozoal structure have also been described. The possibility exists that minor deformities of spermatozoa may not interfere with their viability but early or late genetic damage could not be ruled out. The most commonly observed form of morphological damage in the testis is the production of large polyploid cells during the late spermatocyte and early spermatid phases of development. A clear-cut example of morphological damage results from treatment with deuterium oxide, which is considered to induce a morphological change in the structure of the acrosome, so that the normal process of fertilization is impaired. Early genetic damage . The most obvious form of genetic damage sustained by the germinal system is that resulting in deaths during early embryonic life. This may be due either to failure of fertilized eggs to implant or to death after implantation. Many instances of reported sterility after treatment of the male may be the result of this type of damage, and for potential antifertility agents it would be essential to know if this is so, since lower doses may induce late genetic damage. Measurement of dominant lethal action may be made in early embryos. Most of the alkylating agents produce some degree of early genetic damage. In the particular case of the simple alkyl alkane sulphonates such as methyl, ethyl, and n -propyl methane sulphonate, the main type of damage produced is directed towards the adult spermatozoa in such a way that the resulting fertilized egg fails to cleave normally, and both pre- and postimplantation deaths occur. The bis(dichloroacetyl)diamines and all antimetabolites should be suspected of causing some degree of early genetic damage, but except for some work in insect spermatogenesis, there is no satisfactory proof of such damage in the higher animals. Late genetic damage . Damage to offspring of treated males has been conclusively demonstrated with triethyleneimine, nitrogen mustard, and methyl methane sulphonate. Owing to the very tedious nature of the experiments, very few drugs have been rigorously studied from this point of view. In general, those drugs which produce changes in DNA structure, such as the alkylating agents and some antimetabolites, as well as those which have already shown some early genetic damage at higher dose levels, may be suspected of producing late genetic damage. Matrix damage . This occurs in some instances in association with extensive damage to the germinal epithelium, as with ethylene urea and ethylene urethane. The progestens, methylhydrazine derivatives, and cadmium salts also show extensive damage to the matrix, and in the case of the last mentioned agent, the testicular structural tissue may be the primary site of action. An interpretation of the action of any new group of cytotoxic substances must take into account the possibilities that the effects observed may be the result of a direct action of the agent on the cell or an indirect one mediated through some of the many complex hormonal and other regulatory pathways in the whole organism. To unravel this complex question is probably easier in the testis than in any other differentiating system in the mammal, since the cellular kinetics of the spermatogenic epithelium, at least in the rodent, is now well known. The interrelationships of this system with the pituitary-gonadal axis is becoming clearer, and a way is opening to understand the mechanism by which the whole organism may control the functioning of one of its component systems. It is clear that the final definition of the mode of action of a drug must involve basic biophysical and chemical mechanisms at the level of a single molecule or a small group of molecules that are essential biochemical foci of action, whether they be at gene or cytoplasmic level. An important technical advance in this field would be the separation of the component cells of the testis by some physical method of centrifugation, countercurrent, or filtration, destroying as little as possible of the enzyme activity, so that detailed biochemical investigations involving cell component separations may be effected. Continued study of the spectrum of drug action on spermatogenesis is desirable, however, since apart from recognizing new drug specificities of action, the potential interest to the emergency problem of population control cannot be overstressed.