The adaptive response of the liver to phenobarbital is characterized by a strong cell hypertrophy and coordinate induction of specific P450 forms (IIB1, 2; IIC7, IIIA1). The pattern of active mRNA is significantly changed, demonstrating the establishment of PB phenotype. Employed as a promoting agent in experimental hepatocarcinogenesis, PB triggers a significantly different, uncoordinated response. Only P450 IIB1 is positively modulated while P450 IIC7 mRNA becomes repressed. Mechanisms underlying the differential P450 adaptative response to PB in the initiated versus non-initiated liver are discussed in the light of both the importance of epigenetic events and the possible role of P450 mono-oxygenases in hepatocarcinogenic promotion by PB.

Vasoactive Intestinal Peptide (VIP) is able at the concentration 10 to 100 nM to induce in HT-29 cells 2'5' oligoadenylate (2'5' A) synthetase activity. The kinetics of this induction show that the maximal effect is attained after 24 hrs. VIP induces 2'5' A synthetase parallel to inhibition of vesicular stomatitis virus growth. The levels of these two induced activities after VIP treatment are comparable to those induced by the poly (I).poly (C), an inducer of IFN beta/alpha in mammalian cells. Moreover the anti-IFN beta/alpha antibodies abolish the VIP-induced 2'5' A synthetase whereas anti-IFN gamma antibodies are ineffective. The fact that VIP establishes an antiviral state in HT-29 cells potentiates new pharmaceutical applications for this neuropeptide.

Whereas a great number of mutations located in the coding regions of genes have been described, genetic defects involving regulatory elements (cis-) or diffusible effectors controlling gene expression (trans-) are poorly known. Moreover, it appears that the structural defects of transcribed regions of genes have already delivered their "conceptual" message, whereas few studies of the consequences of one single gene defect on the expression of other genes and on in vivo functions are available. In the present communication, we wish to address the following issue: can we take advantage of Nature's experiments, ie. diseases, to extend our knowledge of the coordinate regulation of gene expression, via an original pathway, ie. the pathophysiological pathway? Can we select a few inborn or acquired metabolic diseases as models which could provide insight into as yet unknown factors involved in trans- regulation of gene expression?

A state of pure vitamin A deficiency, without any clinical manifestations, rapidly induces a stimulation of ornithine decarboxylase (ODC) activity and some oesophageal mucosal abnormalities (hyperkeratosis, dyskeratosis, cytonuclear abnormalities) in rats treated with N-nitrosobenzylmethylamine (NBMA). Retinol deficient rats fed with retinoïc acid (all-trans) show a mucosal ODC induction, but no morphological lesion. The association of retinoïc acid + retinol, as does retinol alone, prevents simultaneously histological lesions and enzymatic induction. In the liver of vitamin A deficient rats treated with NBMA, a stimulation of the ODC system, without any macroscopical lesions, has been observed.

In the previous study, it was shown that the treatment of human neuroblastoma cells with human interferon-gamma (HuIFN-gamma) induced the morphological changes. However, the treatment with human interferon-alpha (HuIFN-alpha) or -beta (HuIFN-beta) did not induce them. In the present study, the effect of HuIFNs on the overexpression of N-myc of the human neuroblastoma cells (GOTO strain) is examined. The treatment of GOTO cells with rHuIFN-gamma inhibits the overexpression of N-myc, and its degree is dependent on the duration of the treatment. However, HuIFN-alpha and HuIFN-beta did not inhibit the overexpression of N-myc. This suggests that the oncogene N-myc may have relation to the morphological differentiation of human neuroblastoma cells because only the HuIFN-gamma, which induces the morphological differentiation, inhibits the overexpression of N-myc.

Cefpiramide (SR 95445) (CPM) is a new cephalosporin with activity against Pseudomonas and a good bioavailability following parenteral administration. This drug is a first rather than second choice treatment in Pseudomonas infections. For this reason, investigation into cefpiramide's capacity to induce beta-lactamase production is especially interesting. A heavy inoculum of P. aeruginosa NCTC 8203, a strain that produces and inducible cephalosporinase (pI = 8.7) was incubated for 4 hours with CPM, cefsulodin (CFS), cefoperazone (CPZ) and ceftazidime (CTZ) in various concentrations. After collection and sonic treatment of the bacteria, the beta-lactamase activity was assayed using an acidimetric method and expressed as units of enzyme activity per mg proteins in the cell-free extract. The smallest increase in beta-lactamase production was recorded with CPM. The strongest inductor was CTZ. CFS and CPZ had an intermediate effect.

Plasma levels of gamma-glutamyl transpeptidase were measured prospectively in 75 epileptic patients treated with one of the following drugs: phenobarbitone (n = 20), phenytoin (n = 23), carbamazepine (n = 18) or sodium valproate (n = 14). A significant increase in gamma-glutamyl transpeptidase levels was observed from the 7th day of treatment onward. The increase was particularly pronounced in the phenytoin group, with mean and maximum values of 104.10 and 215 mU/ml respectively, followed by the phenobarbitone group (mean 68.15, max. 124 mU/ml), the carbamazepine group (mean 49.83, max. 100 mU/ml) and the sodium valproate group (mean 35.42, max. 70 mU/ml). This was due to enzyme induction being highest with phenytoin and phenobarbitone which are strongly liposoluble and have prolonged half-life. Any epileptic patient with plasma gamma-glutamyl transpeptidase levels higher than those found in this study may be suspected of having viral or alcoholic hepatitis.

Study of the biosynthesis of NADH: rubredoxin oxidoreductase in resting cells of Clostridium acetobutylicum shows that this enzyme is synthesized at a maximal rate in the presence of acetic acid at a concentration of 3 g . l-1 and at pH 4.8. Protons do not play any role in this biosynthesis since no induction is observed in a medium without acetate for the same values of pH. Butyric acid at a concentration of 0.5 g . l-1 gives 50% induction and formic acid, isobutyric acid and propionic acid have no inductive action on NADH: rubredoxin oxidoreductase. These results are confirmed by studies using a dialysis bag. Only a culture against acetic acid at an initial concentration of 2 g . l-1 gives maximal biosynthesis of the enzyme, whereas a culture in which all products of metabolism are eliminated gives an activity which is 80% lower.

After stimulation of human lymphocytes by 12-0 tetradecanoyl phorbol acetate (TPA) and by the calcium ionophore A23187 an early transient expression of proto-oncogene fos followed by an expression of c-myc is observed, as has been described in rodent fibroblast stimulated by growth factors. This observation suggests a direct role of protein Kinase C and of calcium flux an the induction of cellular oncogenes fos and myc that may be associated with the early steps of activation and proliferation of lymphocytes.

Inducers of cytochrome P450-linked mono-oxygenases increase the normobaric oxygen tolerance of the adult rat. Pulmonary inducers, as 3-methylcholanthrene and beta-naphthoflavone permit the rat survival and simultaneously a decrease of pulmonary edema. Phenobarbital, an hepatic inducer had lesser effects both on survival rate and on pulmonary and lymphoïd oxygen toxicity.

Glutathione peroxidase (Se-GPx) is a selenoenzyme which catalyzes the reduction of hydroperoxides by glutathione (GSH), in most mammalian cells. Several Slow-acting drugs that are used in the treatment of rheumatoid arthritis, including D-Penicillamine, alpha-mercaptopropionylglycine and gold salts, are specific inhibitors of Se-GPx. In situation of oxidant stress, Se-GPx activity is a major source of glutathione disulfide (GSSG), an essential activator of leucocyte collagenase. Hence the possibility that the enzymatic reduction of hydroperoxides produced during chronic inflammation would play an important role in the destruction of joint tissue of arthritic patients. Inhibition of a protective system such as Se-GPx may therefore be involved in the mechanism of action of D-Penicillamine and gold salts, but it could also explain some of their undesirable or toxic effects. Confirmation of this hypothesis would open the way to new pharmacological strategies.

The rat pituitary tumor derived cell lines of the "GH" family offer a fruitful model for studying the expressions of the prolactin (rPRL) and growth hormone (rGH) genes in basic and regulated states. In order to assess the potential role of DNA methylation in the basic expressions of rPRL and rGH genes we have used different cell strains which produce either high level of rPRL (GH3B6 cells) or of rGH (GC cells) and minute amounts of both hormones (GH3CDL cells). The cleavage patterns generated by the methylation sensitive enzymes Hpa II and Msp I indicated an inverse correlation between the extent of gene methylation and the level of expression. However the use of 5-azacytidine which decreases DNA methylation suggested a variable importance of gene methylation in the respective control of rPRL and rGH genes depending on the cell lines. In an other hand we attempted to elucidate some of the mechanisms by which thyroliberin (TRH) enhances rPRL gene transcription in GH3B6 cells. Preliminary results indicated that the persistent occupancy of the TRH receptors was required to sustain at least for the first 5 hours the increased rate of rPRL gene transcription. In addition the possible relationship between the TRH-induced acute rPRL release and the stimulation of rPRL gene transcription was investigated. The results suggested that the activators of the C kinase-mediated pathway which are actually involved in the stimulation of the acute release were not sufficient alone for eliciting the maximum TRH response at the gene level.

To know the intensity of liver enzyme induction during a treatment with anticonvulsant, the authors have measured gamma GT before and at the 7th, 30th, 60th days after a treatment by one of the 4 major anticonvulsant as phenobarbital, diphenylhydantoin, carbamazepine and sodium valproate. All alcoholic patients, and all the patients having a liver disease have been eliminated. The results show that diphenylhydantoin is the most important inductor of gamma GT with an elevation that can reach 312% of basal level, followed by phenobarbital, when sodium valproate and carbamazepine are the weakest inductors. More, induction by carbamazepine in women is more weak than in man. Age takes a place in intensity of induction with a major induction observed between 30 and 50 years old for phenobarbital, and above 50 years old for sodium valproate. These effects are not dependent of an hepatitis. The knowledge of the upper levels of gamma GT induction by anticonvulsant appear to us usefull for several reasons: carbamazepine and sodium valproate being the weakest inductors, they must be chosen in priority in women under contraceptive treatment. Any abnormal elevation of gamma GT need to look of an alcoholic intoxication, an hepatitis or a liver cancer.