Structure-activity relationships in polycyclic aromatic hydrocarbons: induction of microsomal aryl hydrocarbon hydroxylase and its possible importance in chemical carcinogenesis

The results of quantitative structure-activity analysis show that the potency of polycyclic hydrocarbons as inducers of microsomal arylhydrocarbon hydroxylase (AHH) can be quantitatively described in terms of hydrophobic interactions, chemical reactivity, and the ability to participate in charge-transfer interactions. The rate-determining step in enzyme induction is probably the formation of a reactive K-region metabolite of the hydrocarbons which then reacts with a specific repressor. The same mechanism is proposed for chemical carcinogenesis on the ground of similarities in structure-activity relationships for both processes. It is suggested that AHH induction is the first step in chemical carcinogenesis.     

Roles of UDP-glucuronosyltransferases in chemical carcinogenesis

UDP-glucuronosyltransferases (UGT) play a major role in the elimination of nucleophilic metabolites of carcinogens, such as phenols and quinols of polycyclic aromatic hydrocarbons. In this way they prevent their further oxidation to electrophiles, which may react with DNA, RNA, and protein. They also inactivate carcinogenic, N-oxidized metabolites of aromatic amines. Furthermore, glucuronides may be stable transport forms of proximate carcinogens excreted via the biliary or urinary tract, thereby liberating the ultimate carcinogen at the target of carcinogenicity. Isozymes of the UGT enzyme superfamily that control the glucuronidation of metabolites of aromatic hydrocarbons and of N-oxidized aromatic amines have been identified in rats and humans. Phenol UGT appears to be coinduced with other drug-metabolizing enzymes via the Ah or dioxin receptor. This isozyme probably controls various proximate carcinogens and contributes to the persistently altered enzyme pattern, leading to the "toxin-resistance phenotype" at cancer prestages. Knowledge about UGTs in different species, their regulation, and their tissue distribution will improve the risk assessment of carcinogens.     

Hyperplastic foci in chemical carcinogenesis]

Morphological, histochemical and biochemical perculiarities of liver hyperplastic nodules induced by different chemical carcinogens are regarded. The presence of basophylic atypical cells in the hyperplastic nodules, the possibility of transplantation of some nodules, the irreversibility of some morphological and biochemical lesions in these allows to designate hyperplastic nodules as a neoplasm. Enzyme and isozyme patterns in hyperplastic vesicles, the appearance of alpha-fetoprotein in these, and some other metabolic findings suggest biochemical disdifferentiation occurring in the vesicles. These findings suggest that cells of hyperplastic nodules are intermediate between normal and malignant cells in the course of neoplastic transformation.     

Serum lipoproteins during chemical carcinogenesis

1. The serum-protein and -lipoprotein patterns of rats, given a purified diet containing 0%, 0·005% or 0·03% 2-acetamidofluorene, have been determined by disk electrophoresis. 2. An abnormal high-density lipoprotein was detected from the first week of the experiment in the serum of the animals given the carcinogen. The low-density lipoproteins also increased on prolonged feeding with the carcinogen.     

Selenium inhibition of chemical carcinogenesis

In this article I review the work of our laboratory concerning the relationship between dietary Se intake and susceptibility to mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in female rats. The effect of graded levels of Se in the diet was investigated, ranging from deficiency to excessive supplementation that produced marginal toxicity in the animals. In addition, the interdependence between Se status and fat intake was also explored. Further experiments were aimed at defining the role of Se in the initiation and promotion phases of chemical carcinogenesis. In view of the biochemical function of Se as an antioxidant, the chemopreventive efficacy of Se was compared to that of vitamin E in conjunction with their ability to inhibit lipid peroxidation. Results of this study indicated that the antitumorigenic activity of Se could not be accounted for by suppression of tissue peroxidation, although an environment with a lower oxidant stress might enhance the potency of Se in protecting against cancer. The possible mechanisms of action of Se based on the observations and characteristics of several tumor models are briefly discussed.     

Protein expression profiling in chemical carcinogenesis: a proteomic-based approach

The simultaneous analysis of a wide array of proteins may provide valuable information on the activation and suppression of cellular systems at different stages of the exposure-disease continuum. In this review, results of proteomic studies in the field of toxicology are covered, focusing on the effects of chemical carcinogens. So far, alterations of highly abundant proteins have been identified which, irrespective of the wide differences in study design and technologies used, can be grossly assigned to three functional classes: proteins related to cellular stress response, inflammation, and stimulation of the immune system. It is obvious that the observed protein alterations are not causal factors in the development of chemically induced cancer but rather reflect common reactions to cellular perturbations. In order to gain deeper insights into the process of chemical carcinogenesis, the previously applied "shotgun" analyses have to be abandoned in favour of targeted proteomic approaches focusing on the accurate identification and quantification of selected proteins. Advanced analytical techniques such as selective reaction monitoring (SRM) and multiple reaction monitoring (MRM) offer this opportunity. If toxicoproteomic research moves into that direction and takes advantage of such techniques it will have the potential to contribute to the elucidation of chemical carcinogenesis.     

Changes in antitumor resistance during chemical carcinogenesis

Subcutaneous injection of 4 mg DMBA to noninbred rats leads to a considerable decrease in host resistance to cancer, which progresses with tumor growth. The rats with inhibited host resistance to cancer accepted well, at the stage of tumor germ, the DMBA-induced tumors from other animals, permitting them to grow--the phenomenon that was not observed in normal noninbred young rats. At the stage of clinically demonstrable nodules at the sites of DMBA injections, the tumors with different transplantability did not only get adapted but developed distant metastases in part of the animals.     

Lipid peroxide metabolism in chemical carcinogenesis]

Lecithin and kephalin content in the microsomes and mitochondria of the rat liver, and also the activity of enzymatic and nonenzymatic systems of the phospholipid peroxidation showed a sharp change following 3,4-benzpyrene injection. Carcinogenesis is accompanied by significant changes in the lipid peroxides content and in the activity of the enzyme utilizing lipoperoxides (glutathion peroxidase, glutathion reductase). Accumulation of lipid peroxides in the rat liver in carcinogenesis was connected with disturbed balance of the generating systems and detoxication of lipid peroxides in the tumour is attributed to the high activity of the protective enzymatic systems and serves as a reflection of the adaptation mechanisms directed to the maintenance of a high pool of proliferating cells in the tumour.     

Structural genomics and its importance for gene function analysis

Structural genomics projects aim to solve the experimental structures of all possible protein folds. Such projects entail a conceptual shift from traditional structural biology in which structural information is obtained on known proteins to one in which the structure of a protein is determined first and the function assigned only later. Whereas the goal of converting protein structure into function can be accomplished by traditional sequence motif-based approaches, recent studies have shown that assignment of a protein's biochemical function can also be achieved by scanning its structure for a match to the geometry and chemical identity of a known active site. Importantly, this approach can use low-resolution structures provided by contemporary structure prediction methods. When applied to genomes, structural information (either experimental or predicted) is likely to play an important role in high-throughput function assignment.