A 44 year old female, previously on propranolol, phenytoin and phenobarbital, developed hepatotoxicity while on sulindac and acetaminophen containing analgesic. A limited review of hepatotoxicity and drug interactions of sulindac is presented. The possible mechanism of hepatotoxicity and its treatment is suggested.

Inducer-mediated differentiation of MELC provides a model to define the cellular and molecular mechanisms involved in terminal cell differentiation (Fig. 2). (Formula: see text) Fig. 2. HMBA-mediated cellular and molecular changes during induced MELC terminal erythroid differentiation. See text for detailed discussion. HMBA-induced differentiation is accompanied by an acceleration of transcription at the alpha 1 and beta maj globin loci. MELC are virus-transformed cells blocked in erythroid lineage development. MELC have acquired a pattern of DNA hypomethylation, nuclease sensitivity, and partially disrupted nucleosome configuration of the chromatin containing the transcriptionally inactive alpha 1 and beta maj globin domains, which distinguish them from the domains of nonerythroid transcribed genes, e.g. immunoglobulin or albumin, or ribosomal RNA genes which are actively transcribed in uninduced cells. HMBA-mediated MELC differentiation is associated with changes in chromatin configuration, characterized by an increased disruption of the nucleosome structure across the structural nucleotide sequences of alpha 1 and beta maj globin genes and the appearance of nuclease hypersensitive sites 5' upstream from the alpha 1 and beta maj genes. The alteration in chromatin structure appears to precede increased transcription of these genes. Inducer-mediated loss of proliferative capacity involves a complex multistep process during which the cells accumulate factor(s), probably mRNA(s), required for the synthesis of proteins which are, in turn, required for expression of the commitment process and activation of globin gene transcription. Characterization of these genes whose expression is modulated in HMBA-induced commitment to terminal cell division is in process.

Mycotoxin problems are one of great concern to health scientists. Toxic fungal metabolites such as aflatoxins, trichothecenes, zearalenone and others are contaminated in our environments and induce various diseases. In this manuscript, the author will summarize the recent advances on toxicology of mycotoxins in special references to toxicological characters, cytotoxicity, genotoxicity (mutagenicity and carcinogenicity), metabolism, and biochemical mode of action. Interaction of mycotoxins with cellular components will be reviewed in order to clarify the toxicological characteristics of mycotoxins such as aflatoxins, trichothecenes, zearalenone, toxic peptides, and anthraquinoid mycotoxins.

The present status of catabolite repression is summarized with respect to the involvement of cyclic AMP and other mediators. A model is presented which may account for the relationship between positive control of gene expression exerted by cAMP and its receptor, CAP, and negative control of catabolite repression mediated by specific metabolites.

Vitamin D must be metabolized to 25-OH-D3 or calcidiol in the liver and subsequently to 1,25-(OH)2D3 (calcitriol) in the kidney to produce its physiological actions. Calcitriol stimulates calcium and phosphorus transport reactions in the small intestine and together with parathyroid hormone stimulates calcium transport reactions in bone and kidney. In the small intestine calcitriol brings about its response in a complex manner. It provides a very rapid response on existing villus cells, causing a rise in calcium transport within 6 h postadministration. This transport response subsides by 18 h, and a second response makes its appearance at 24-48 h. This second response is likely to be an action on crypt cells which then migrate into the villus region and bring about calcium transport. The molecular mechanism of calcium transport in the villus cells has been examined. Calcitriol localizes specifically in the nucleus within 0.5 h postadministration, and it does not localize in any of the other cell fractions. A receptor has been discovered for calcitriol, and interaction with this receptor is required for calcitriol to bring about its action in stimulating calcium transport. It is therefore believed that calcitriol, together with receptor, binds to specific portions of nuclear DNA to bring about transcription of specific genes that code for calcium and phosphorus transport proteins. Only one protein induced by calcitriol has been described. It is the calcium-binding protein found in the cytoplasm. Exactly how it functions in calcium transport is in debate, although the time sequence of its appearance appears to be consistent with a role in that system. It is likely that other gene products are induced by calcitriol, and they are currently being characterized. In the neonatal rat, active calcium transport does not make its appearance until 14-16 days postpartum. The intestine is not sensitive to vitamin D or calcitriol prior to this time. This lack of sensitivity is because of the lack of a receptor for calcitriol. The receptor to calcitriol can be precociously induced by hydrocortisone injections, or it can be delayed by adrenalectomy. Incubation of intestine from neonatal rat pups at 14 days postpartum with hydrocortisone brings about in vitro appearance of the receptor molecule. These results and results of studies involving genetic vitamin D resistance strongly suggest that calcitriol must function by interaction with the receptor, presumably by a nuclear mechanism, to bring about intestinal calcium transport. The molecular mechanism, however, remains to be described.

5-Azacytidine transiently augments fetal hemoglobin production in patients with beta-thalassemia or sickle cell anemia. This change would probably be beneficial to such patients (e.g. a normal fetal gene product is substituted for a deficient or defective adult gene product) if HbF production could be sustained at high levels for prolonged periods. Even though the clinical use of 5-azacytidine is limited because of its presumed potential to cause cancer, studies with this drug have provided new insights into globin gene regulation and have stimulated the development of other strategies to increase HbF synthesis.

Biological actions of 4 commonly used synthetic antioxidants--butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and propyl gallate--on the molecular, cellular and organ level are complied. Such actions may be divided into modulation of growth, macromolecule synthesis and differentiation, modulation of immune response, interference with oxygen activation and miscellaneous. Moreover, an overview of beneficial and adverse interactions of these antioxidants with exogenous noxae is given. Beneficial interactions include radioprotection, protection against acute toxicity of chemicals, antimutagenic activity and antitumorigenic action. Possible mechanisms of the antitumorigenic action of antioxidants are discussed. This discussion is centered around antioxidant properties which may contribute to a modulation of initiation-related events, especially their ability to interfere with carcinogen metabolism. The beneficial interactions of antioxidants with physical and chemical noxae are contrasted to those leading to unfavorable effects. These include radiosensitization, increased toxicity of other chemicals, increased mutagen activity and increased tumor yield from chemical carcinogens. At present, the latter one can most adequately be characterized as tumor promotion at least in the case of butylated hydroxytoluene. It is concluded that current information is insufficient to promote expectations as to the use of antioxidants in the prevention of human cancer.

Glucocorticoids control the expression of a small number of transcriptionally active genes by increasing or decreasing mRNA concentration. Either effect can result from a transcriptional or a post-transcriptional mechanism. Induction of mouse mammary tumour virus RNA results from a stimulation of transcription initiation and depends on the presence of defined regions in proviral DNA. These regions bind the glucocorticoid receptor and behave functionally as proto-enhancers. Glucocorticoid-inducible genes can retain their sensitivity to the hormone after transfer to a heterologous cell by transfection techniques. Non-inducible genes can become inducible when linked to the promoter region of an inducible gene. The mechanisms by which the receptor-steroid complex stimulates or inhibits transcription or influences mRNA stability are unknown. Receptor binding to nucleic acids appears to be a necessary but not sufficient condition. It is likely that the receptor also interacts with chromatin proteins. This might lead to a catalytic modification of these proteins, resulting in a modulation of gene expression. Development of glucocorticoid-sensitive, biochemically defined, cell-free transcription systems should provide a tool to delineate the molecular determinants of this essential regulatory mechanism.

The main attention is paid to the critical analysis of experimental data on morphogenetically active substances, so called "morphogens". It is proposed to consider the morphogens as specific transmitters providing for definite phases of morphogenetic tissues interactions, rather than as vectors of "morphogenetic information". In the normal development, the most studied morphogenetic tissue interactions can be referred to as so called permissive inductions, since the cells of the vertebrate embryos (amphibians, avians) are early determined for development in the ectomeso--and endodermal directions. A slow progress in studying the morphogens can be due to the following causes. 1. Theoretical "inadequacy" of the former concepts on the essence and mechanisms of embryonic induction. The necessity to develop a new system of concepts in this area of developmental biology is stressed. 2. Incompleteness of knowledge about the properties of reacting tissues and the mechanisms of action of morphogens. The early gastrula ectoderm of amphibians, most frequently used for testing the morphogens, appears to be a heterogenous population of the cells with different properties and potencies. It is, therefore, impossible to standardize strictly the biotesting of morphogens. It is suggested that the use to this end of aggregates of cell "strains" from the gastrula ectoderm, rather than of the gastrula ectoderm itself, may be more adequate 3. Insufficiency of embryonic material for biochemical identification and isolation of natural morphogens. A study of so called heterogenous inductors might be of help; these latter can be considered as analogs of natural morphogens. But the similarity of natural and heterogenous inductors can be limited only by their final effect on target tissue. The data are provided on the chemical nature, properties and mechanisms of action for a number of natural and heterogenous inductors (vegetalizing, neuralizing, mesodermalizing, lens-inducing factors). A conclusion is drawn that specific antigens do exist normally but they should not be established as a special class of "informationally important" molecules. The information necessary for development is contained in target cells and the function of a morphogen consists in providing for a definite link in the chain of processes leading to the switching on or expression of one or another programme. Only syntheses of specific proteins can, apparently, be programmed, thus reflecting the "onset" of differentiation path for a cell.

Within the very large group of sickle cell hemoglobinopathies several phenocopy clusters exist. These can be conveniently classified as: 1) conditions in which HbA and S are present, 2) disorders where HbS is the predominant hemoglobin, and 3) the HbSF phenotype. This review will focus on distinguishing the genotype of these common phenocopies as well as new potential approaches to therapy.