The switch-off of nitrogenase by ammonia in cells of the purple bacteria is not due to the conversion of nitrogenase into an inactive form. The latter is probably an initial stage of the enzyme degradation in the presence of excess nitrogen.

"Reinforcing" effects are ascribed to endogenous opioids, particularly to the pro-opiomelanocortin (POMC)-derived beta-endorphin 1-31, the most potent opiate-active substance. Alcohol induces variations in the genetic processing of the precursor POMC and of beta-endorphin at different levels. Studies focused on changes in POMC gene expression (mRNA quantitation) and post-translational processing. Chronic alcohol intake significantly reduces POMC mRNA in the lobes of the pituitary. In inbred strains of mice, genotypic differences are seen in post-translational processing of hypothalamic beta-endorphin, thus inducing differences in alcohol sensitivity. Clinical studies show a disproportion of POMC cleavage products in the CSF of chronic alcoholics (reduced beta-endorphin versus increased ACTH contents), together with remarkable indications for baseline differences in beta-endorphin levels. Errors within the genetic sequence of POMC are suggested to underlie alcohol-seeking behavior.

Animal cell growth factors stimulate expression of the proto-oncogenes c-myc and c-fos. The products of these genes seem to act as intracellular mediators of the mitogenic response to growth factors. Phosphatidyl inositol breakdown products function as cytoplasmic second messengers to induce transcription of c-myc and c-fos although they may not play an exclusive role in this regard. Post-transcriptional events may contribute to the modulation of c-myc gene expression. Following induction, the c-myc and c-fos mRNAs are selectively degraded within the cell.

The elements that we have identified in the 5'-flanking region of the rat growth hormone gene are shown in Figure 7, and the following conclusions are drawn: 1) Cell-specific expression of the rat growth hormone gene is mediated by two CSEs, which are located from -95 to -65 and from -137 to -107.2) These CSEs bind a common cell-specific trans-acting factor (GH-CSF), which is found in growth hormone-producing cells. 3) Enhanced levels of cell-specific expression may involve a protein-protein interaction when this factor binds on the same side of the DNA helix as the two CSEs. 4) A TRE is located between -208 and -178. 5) Activation of the gene by thyroid hormone appears to require both the TRE and one of the CSEs, and both are required to confer L-T3 stimulation to several heterologous promoters. 6) Our studies support the notion that stimulation by L-T3 involves the binding of the L-T3-receptor complex to the TRE, which enhances the function of the CSEs, resulting in stimulation of growth hormone gene expression.

Steroid hormones modify several brain functions, at least in part by altering expression of particular genes. Of interest are those genes that are involved in cell-cell communication in the brain, for instance neuropeptide genes and genes that code for enzymes involved in synthesis of neurotransmitters. Steroid regulation of mRNA levels for several genes has been reported, including the genes coding for the neuropeptides vasopressin, corticotropin releasing factor, luteinizing hormone-releasing factor, pro-opiomelanocortin; somatostatin, preproenkephalin, and the enzyme tyrosine hydroxylase. Steroid control of releasing factor genes is consistent with classical neuroendocrine concepts of negative feedback. Steroid-induced plasticity of gene expression is sometimes in evidence, with the presence or absence of a particular steroid inducing expression of a neuropeptide gene in neurons that under other conditions do not express the gene. As a means of gaining some insight into the mechanism of action of steroid hormones, several groups have determined some of the neuropeptide profiles of neurons that contain receptors for steroid hormones. Marked heterogeneity is found, in that often only a subpopulation of phenotypically-similar neurons, even within a single brain area, contains receptors for a given steroid.

ODC, the first enzyme in mammalian polyamine biosynthesis, is rapidly induced in response to a wide variety of growth stimuli. However, there is no single mechanism which may explain the rapid turnover of ODC activity. ODC activity has been shown to be regulated at the level of synthesis and degradation, and also by post-translational modifications and an interaction with macromolecules. Our results indicate that TPA-induced ODC activity is regulated at the transcriptional level. An initial signal in ODC induction by TPA is not clear. We have suggested that TPA-increased accumulation of epidermal prostaglandins is required, but not sufficient, for ODC induction by TPA. Others have suggested the role of lipoxygenase product(s) in ODC induction. The role of the microtubule-containing system in regulation of ODC induction has been shown. The involvement of cyclic nucleotides in ODC induction by TPA is controversial. Also, generation of free radicals appears to be involved in ODC induction by TPA. Data summarized in this chapter indicate that activation of PKC may be an initial step in ODC induction by TPA.

Advances in molecular biology over the last few years have made it possible to extend studies concerned with the role of renin in blood pressure regulation and fluid balance to the genetic level. Epidemiological data from cross-sectional population studies as well as experimental findings in spontaneously hypertensive rats suggest a greater disposition towards hypertension in males than in females. Testosterone (T) is known to raise blood pressure in female and castrated male SH-rats, while concomitantly increasing tissue renin activities. The availability of recombinant DNA technology and of a 32P labeled mouse submandibular gland renin cRNA as a hybridization probe enabled us to quantitatively assess whether this increase is paralleled by enhanced renin gene expression. In groups of female NMRI mice injected with DHT, we were able to show, that cardiac renin activity was significantly increased after 2 hours (1.6 fold) and 21 days (1.9 fold) of dihydrotestosterone (DHT) treatment compared to controls. DHT had no effect on renin mRNA concentration in the uterus, whereas in the ovary it resulted in a 50% decrease. We conclude that enhanced renin-activity and mRNA levels in peripheral organs and in the central nervous system are due to direct or indirect effects (cis, transacting) of T on renin gene expression. Thus, T may participate in the development of hypertension by stimulating the activity of tissue renin-angiotensin systems.

Current investigations of modifications of metabolic activation of carcinogens by the environmental chemical factors which are able to induce or inhibit the metabolic activation are reviewed. From the standpoint of ecological oncology the most promising are the following trends: 1) modelling under experimental conditions of integral ecosystems including the complex of living organisms, environmental carcinogens, and factors which modify their biotransformation; 2) study of the imprinting effectors of metabolism modifiers; 3) detection in the environment of modifiers of metabolic activation of carcinogens. The comprehensive oncological-ecological studies of chemicals which influence different pathways of carcinogen metabolism are very important for both primary prevention of cancer and the environmental protection.

1. Observations of drug metabolism enzyme induction in animals during early toxicological trials, and phase I or II of clinical trials, are of importance for the development of a new chemical of pharmacological interest. 2. Induction can be detected by determination of enzyme activities or enzyme proteins in tissues (subcellular fractions or cells in culture). 3. Indirect methods for checking induction can involve determinations of endogenous (i.e. glucaric acid, 6-beta-hydroxycortisol) or xenobiotic (antipyrine) metabolites which are produced by the inducible enzyme systems. 4. Recent progress in the knowledge of biochemical mechanisms of induction and the large number of identified isoenzymes in each enzyme 'family' have complicated the interpretation in pharmaco-toxicological studies. 5. This paper describes the present state of the art concerning the relationships between the isoenzymes and the major classes of inducers concerning cytochromes P-450, UDP-glucuronosyltransferases, gamma-glutamyltransferase and epoxide hydrolases.