Retinoic acid, unlike the naturally occurring vitamin A (retinol), is a minor component of the human diet. It is formed in vivo from retinol and has many metabolites. The biological activity of the metabolites is not higher than that of retinoic acid itself, indicating that the metabolites must be products of retinoic acid catabolism. Little is known about the enzymatic systems responsible for forming retinoic acid or about how it enters the cell. Discovering the molecular mechanism(s) of retinoic acid activity in cellular metabolism is important to understanding its physiologic role. The pharmacologic effects of high doses of retinoic acid may be caused by its action on cellular membranes. Conversely, low concentrations appear to produce physiologic effects. Results of experiments with animals and with cell cultures indicate that the primary physiologic role of retinoic acid is in cellular differentiation. Retinoic acid influences genomic expression, inducing the appearance of some proteins while suppressing the expression of others. The existence of an intracellular retinoic acid-binding protein suggests that it may mediate the physiologic effects of retinoic acid on cellular differentiation.

Adaptive hyperlipogenesis in the liver occurs after feeding rats a high-carbohydrate, fat-free diet or after treatment with thyroid hormone. This phenomenon is accompanied by the induction of a family of enzymes and proteins involved in various aspects of lipogenesis, resulting largely from alterations in the rates of protein synthesis. The changes in protein production, in turn, are the result of increased or decreased cellular concentrations of specific mRNAs in response to carbohydrate feeding or hyperthyroidism. There is a large degree of overlap between the mRNA species induced by thyroid hormone and carbohydrate feeding in rat liver. One such mRNA species, spot 14, has several attractive features as a potential model for exploring the molecular mechanisms involved in the regulation of gene expression. Most importantly, the mRNA for spot 14 increases with a lag time of less than 20 min after treatment with thyroid hormone or sucrose gavage and thus may represent a primary response to the hormonal and dietary stimuli. Initial studies to elucidate the cellular site of action of thyroid hormone and dietary carbohydrate indicate that changes in both the rate of gene transcription and the stability of the nuclear RNA precursor are involved in spot 14 mRNA induction.

It is likely that most vertebrate genes are associated with 'HTF islands'--DNA sequences in which CpG is abundant and non-methylated. Highly tissue-specific genes, though, usually lack islands. The contrast between islands and the remainder of the genome may identify sequences that are to be constantly available in the nucleus. DNA methylation appears to be involved in this function, rather than with activation of tissue specific genes.

Approaches to the evaluation of drug and other chemical toxicity with mammalian cell culture systems are designed to enhance the predictability of animal models. Identification of toxic agents by in vitro screening tests and studies of mechanisms through which chemicals induce critical lesions at the cellular and subcellular levels help to make those predictions sooner and perhaps single out those target sites and chemicals of most concern.

In the very rare cases where a pregnancy occurs during oral contraceptive use, the blame is usually laid against the patient for having forgotten to take the pill. Evidence has started to accumulate to suggest that neither the patient nor the pill is at fault in some contraceptive failures. It may be because the patient is taking other medicines and these may be preventing the pill from suppressing ovulation. Most drug interactions reducing or negating contraceptive activity are due to concomitant use of drugs having microsomal enzyme-inducing activity (e.g., some antibiotics, especially rifampicin, and anticonvulsants, including phenobarbital, phenytoin, and primidone. Other antibiotics (e.g., tetracycline) may also interact by interruption of the enterohepatic circulation of contraceptive steroids. Less well appreciated, oral contraceptive steroids may themselves modify the metabolism and pharmacological activity of various other drugs (e.g., anticoagulants, benzodiazepines, beta-blockers, caffeine, corticosteroids, and tricyclic antidepressants); in this respect the oral contraceptives are acting as enzyme inhibitors. Contraceptive steroids may also interact with drugs that cause enzyme inhibition and this delays the metabolism of the hormonal agents. Interactions of this type would be expected to potentiate the action of the contraceptive steroids. It is suggested that the effects of such interaction might be presented in terms of increased incidence of side effects, including water retention, diabetogenic effects, hypertension, and an increased risk of thromboembolic disorders. The spectrum of interactions with oral contraceptives is presented in three tables.

The activity of many enzymes that carry out biotransformation of drugs and environmental chemicals can be substantially increased by prior exposure of humans or animals to a wide variety of foreign chemicals. Increased enzyme activity is due to true enzyme induction mediated by increased synthesis of mRNAs which code for specific drug-metabolizing enzymes. Several species of cytochrome P-450 are inducible as are certain conjugating enzymes such as glutathione S-transferases, glucuronosyl transferases, and epoxide hydrolases. Induction of drug-metabolizing enzymes has been shown in several instances to alter the efficacy of some therapeutic agents. Induction of various species of cytochrome P-450 also is known to increase the rate at which potentially toxic reactive metabolic intermediates are formed from drugs or environmental chemicals. Overall, however, induction of drug-metabolizing enzymes appears to be a beneficial adaptive response for organisms living in a "chemically-hostile" world.

Studies with synthetic metal-porphyrin complexes in which the central iron atom of heme is replaced by other elements indicate that those heme analogues that cannot be enzymatically degraded to bile pigments possess novel biological properties that may have considerable clinical as well as experimental value. Such studies have revealed the important role that the central metal atom plays in determining the physiological and pharmacological properties of metal-porphyrin complexes; and they have demonstrated that the form in which animals and humans are exposed to trace metals, i.e., inorganic, organified, porphyrin-chelated, etc., can be of great importance in determining the biological responses that such elements elicit, especially with respect to actions on heme synthesis and degradation and cytochrome P-450 formation and function. Study of the biological properties of synthetic metalloporphyrins represents a potentially fruitful area of research and the results may have significant value for basic as well as clinical disciplines.

The mechanism of action of steroid hormones involves their interaction with tissue-specific binding sites, and results in a precise modulation of gene expression. Both high-affinity receptors and secondary binding sites exist for steroid hormones in target tissues. Only steroid-receptor complexes were, in several cases, clearly shown to directly regulate transcription by interacting with DNA region(s) close to steroid-controlled genes. However other indications suggest that steroid hormones could also modulate transcription by altering chromatin conformation. These modifications encompass post-traductional modifications of histones and non-histone proteins, as well as changes in the pattern of histone variants. Beside transcription, there are also evidences that steroid hormones can modulate gene expression by regulating some RNA processing events. Whether high-affinity receptors or secondary binding sites directly regulate these events is not known. These observations however suggest that several levels of control might exist for steroid hormones to precisely regulate gene expression.