Although their precise mechanisms of action are undefined, the usefulness of CCS in the treatment of asthma is unquestioned. It is clear that they act at multiple sites. Among the general actions of CCS felt to be applicable to asthma are their ability to facilitate beta-adrenergic responsiveness and to suppress inflammation. More specific actions relevant to asthma are their inhibition of eicosanoid formation (e.g., reduction in leukotriene formation), prevention and reversal of LPR (probably through CCS anti-inflammatory effects), and reduction in mucus secretion. Actions that have not yet been clarified but that may be useful include possible reductions in airway hyperreactivity (or at least the prevention of increases in reactivity superimposed upon overreactive airways) and suppression of basophil (but not mast cell) mediator release.

Selenium at nutritional levels has been shown to have numerous anticarcinogenic or preventative effects against carcinogen-induced breast, colon, liver and skin cancer in animals. Many of these anticarcinogenic effects have been summarized. In addition, numerous mutagenic and antimutagenic effects of selenium compounds have been reported. Some of the selenium compounds frequently tested for mutagenicity are listed in Table 1. Because of the numerous reported anticarcinogenic and preventative effects of selenium, many individuals are supplementing their diets with amounts of selenium that are greater than the recommended daily requirement. Selenium is also used widely in industrial products such as selenium rectifiers, photoelectric batteries, alloys and paints. Because selenium at higher levels is known to be toxic, there should be a greater understanding about its genotoxic as well as its beneficial effect. The object of this review is to summarize experimental evidence both for the antimutagenic and the mutagenic effect of selenium.

A constant fine regulation of gene expression is needed for the normal development to proceed and for the physiological homeostasis to be maintained. In many cases such a regulation in eukaryotes is realized at the level of transcription, involving various cis- and trans-regulatory genomic elements. The review provides the data on the structure of elements determining the level of gene transcription in response to the action of various environmental factors and effectors, responsible for coordinated expression of the genes which provide for tissue-specific transcription and self-regulation of gene transcription. The data were considered on regulation of gene activity by mobile genetic elements and a relationship between the mechanisms of regulation of gene expression and evolution has been formulated.

The modern data on Escherichia coli K-12 ilv genes expression are reviewed. The problems of regulation of the ilv genes activity and of their possible role in the process of cell adaptation to changeable environment are discussed.

Numerous reports have illustrated the versatility of polychlorinated biphenyls (PCBs) and related halogenated aromatics as inducers of drug-metabolizing enzymes and the activity of individual compounds are remarkably dependent on structure. The most active PCB congeners, 3,4,4',5-tetra-, 3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl, are substituted at both para and at two or more meta positions. The four coplanar PCBs resembled 3-methylcholanthrene (3-MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in their mode of induction of the hepatic drug-metabolizing enzymes. These compounds induced rat hepatic microsomal benzo(a)pyrene hydroxylase (aryl hydrocarbon hydroxylase, AHH) and cytochromes P-450a, P-450c and P-450d. 3,4,4',5-Tetrachlorobiphenyl, the least active coplanar PCB, also induced dimethylaminoantipyrine N-demethylase and cytochromes P-450b+e and resembled Aroclor 1254 as an inducer of the mixed-function oxidase system. Like Aroclor 1254, all the mono-ortho- and at least eight di-ortho-chloro analogs of the coplanar PCBs exhibited a "mixed-type" induction pattern and induced microsomal AHH, dimethylaminoantipyrine NM-demethylase and cytochromes P-450a-P-450e. Quantitative structure-activity relationships (QSARs) within this series of PCBs were determined by comparing their AHH induction potencies (EC50) in rat hepatoma H-4-II-E cells and their binding affinities (ED50) for the 2,3,7,8-TCDD cytosolic receptor protein. The results showed that there was an excellent correlation between AHH induction potencies and receptor binding avidities of these compounds and the order of activity was coplanar PCBs (3,3',4,4' -tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyls) greater than 3,4,4',5-tetrachlorobiphenyl approximately mono-ortho coplanar PCBs greater than di-ortho coplanar PCBs. It was also apparent that the relative toxicities of this group of PCBs paralleled their biological potencies. The coplanar and mono-ortho coplanar PCBs also exhibit differential effects in the inbred C57BL/6J and DBA/2J mice. These compounds induce AHH and cause thymic atrophy in the former "responsive" mice whereas at comparable or higher doses none of these effects are observed in the nonresponsive DBD/2J mice. Since the responsiveness of these two mice strains is due to the presence of the Ah receptor protein in the C57BL/6J mice and its relatively low concentration in the DBA/2J mice, the results for the PCB cogeners support the proposed receptor-mediated mechanism of action.

Polychlorinated biphenyls, certain polychlorinated dibenzo-p-dioxins and certain polychlorinated dibenzofurans cause a variety of biological effects in experimental animals. The mechanism of the induction of certain enzymes is perhaps best understood. That is, there is binding of certain chlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans to a receptor, translocation of the compound-receptor complex into the nucleus followed by an increased activity of a number of enzymes in the cell. Although the concentration of this receptor in various tissues of some mouse strains correlates well with the intensity of some of the biological effects observed in the mouse strains exposed to these compounds, this correlation apparently does not extend across various species. The current evidence suggests that the acute toxic effects of TCDD in various species is in some way associated with binding of TCDD to the receptor. However, biological effects of TCDD in addition to those resulting from binding to the receptor may be required to produce acute toxicity and, perhaps, other effects. The acute toxic effects of TCDD are probably caused by the parent compound rather than metabolites; however, this conclusion must be viewed as tentative. Also, it cannot be excluded at this time that biological effects other than acute toxicity may be caused by metabolites of TCDD. Finally, the acute toxic effects of TCDD appear not to be related, at least not directly, to the rate of metabolism of TCDD in experimental animals nor to the half-life of excretion.

In chickens, the liver functions in gluconeogenesis to recycle lactate carbon (Cori cycle) and the kidney is the major organ for net gluconeogenesis from substrates such as pyruvate and amino acids. This is markedly different from mammalian systems where the liver is the primary gluconeogenic organ. The limited ability of chicken hepatocytes to synthesize glucose is explained, at least in part, by the observation that phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) in these cells is located exclusively in the mitochondria. The kidney possesses a cytosolic form of this enzyme that adapts to dietary and acid-base stimuli. The relative abundance of mRNA coding for the cytosolic enzyme has been detected by using a specific cDNA probe. Starvation increases the level of this mRNA in chicken kidney and also results in the appearance of the message in chicken liver. Isolated hepatocytes have been used to determine which hormones regulate expression of the hepatic gene. Incubations with glucagon, epinephrine, norepinephrine, dexamethasone, or dibutyryl cyclic AMP increase the relative abundance of the message in liver cells isolated from fed chickens. Despite considerable levels of this mRNA in the liver of starved chickens, functional cytosolic enzyme activity is not detected. This indicates some form of posttranscriptional regulation. The studies summarized illustrate the usefulness of isolated hepatocytes and recombinant DNA probes in the study of hormonal regulation of hepatic gene expression.

The induction of proto-oncogens H-ras-1 by nitrosomethylurea (Sukumar et al. (1983), 306, 658-661) is discussed in term of lack of DNA-repair of lesions induced in DNA by this alkylating agent, particularly O6-methylguanine residues and apurinic/apyrimidinic sites.

The enzymatic methylation of specific cytosine residues in DNA plays a part in controlling gene expression. Low methylation levels may be a necessary condition for gene expression. The chemical carcinogens exert their effect on the enzymatic methylation of mammalian DNA and can cause hypomethylation. Demethylated sites do not become remethylated in the subsequent cell cycles. The consequence of DNA hypomethylation may be both stimulation of cell differentiation and initiation of carcinogenesis.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons are a highly toxic class of environmental contaminants, as evidenced by numerous cases of accidental poisonings of human and animal populations and their extreme toxic potency in laboratory animals. The proposed model for the mechanism of action of TCDD and related compounds is analogous to that of the steroid hormones, which modulate gene expression through a receptor mechanism. In the steroid receptor model, the compound enters the cell cytoplasm where it acts as a specific ligand, binding selectively to a high affinity receptor protein. Bound to the appropriate ligand, the receptor concentrates in the nucleus where its increased association with chromatin leads to altered gene expression. This model has been useful in characterizing the Ah receptor; however, it does not provide a unifying hypothesis for all biochemical and toxic effects associated with exposure to halogenated aromatic hydrocarbons. Several findings suggest that a primary factor in determining TCDD toxicity might be tissue and species specific factors that control the actions of Ah receptor(s) in target tissues. Furthermore, numerous mechanisms might be involved. Clarifying the mechanism(s) for TCDD toxicity would enhance our ability to predict human health consequences to toxic halogenated aromatic hydrocarbons and would provide a more rational basis for risk analysis.

Treatment of serum-deprived fibroblasts with serum or growth factors results in an immediate induction of the c-fos and c-myc proto-oncogenes. Maximal levels of c-fos mRNA are detected 30 minutes after treatment and maximal levels of c-myc mRNA are detected 60 minutes after treatment. The c-fos protein is expressed at high levels for about two hours following induction, yet the cell morphology remains normal. Thus, either an extended period of c-fos expression is required for cellular transformation, or the highly modified form of the fos protein, present in stimulated cells, is biochemically different from the transforming protein and is therefore not capable of inducing transformation. In this system, growth factor treatment results in mitogenesis. However, c-fos and c-myc are also induced in A431 cells, and in subclones derived from A431 cells, treated with epidermal growth factor (EGF). No correlation was found between the effects of EGF on A431 cell proliferation and the induction of c-fos and c-myc. Interestingly, the strongest inducer of c-fos in A431 cells was the calcium ionophore A23187. Induction occurred in almost 100% of the treated cells without prior serum deprivation or growth arrest. Treatment of HL60 cells with 12-0 tetra decanoylphorbol-13-acetate (TPA), which promotes macrophage-like differentiation, also induced c-fos with a time course similar to that observed in mitogen-treated fibroblasts. Thus, in HL60 cells, c-fos induction is associated with differentiation. In normal macrophages c-fos and c-myc can also be induced by CSF-1. However, the kinetics of induction are entirely different from those in growth factor-stimulated fibroblasts. Taken together, the data suggest a more general role for c-fos and c-myc in the transduction of growth factor signals received at the cell membrane, within the nucleus.