Mechanisms of genotoxic effects of hormones

Abstract

A concept that compounds commonly present in biological systems lack genotoxic and mutagenic activities is generally in use, hence a low number of endogenous substances have ever been tested to mutagenicity. Epidemiological and experimental analysis indicated, however, that sexual steroids could contribute to initiation and/or continuation of malign diseases. Detailed studies using methods of biochemistry, molecular biology, cytogenetics and other branches, showed that not only epigenetic mechanisms, such as a stimulation of cell proliferation, but also certain hormones, that can express genotoxic effects, such as covalent DNA modification, then chromosomal lesions and chromosomal aberrations, are in the background of malign transformation under activities of hormones. In the case of oestrogens, it was shown that excessive hormonal stimulation led to a metabolic conversion of these hormones to reactive intermediates with formation of reactive oxygenic derivates, so that cells were virtually under conditions of oxidative stress. Individual and tissue susceptibility to occurrence of deterioration of DNA and other cell components generally results from the differences in efficiency of enzymic and non-enzymic mechanisms of resistance against oxidative stress. Besides, steroid thyeroid hormones and catecholamine (dopamine, noradrenaline/norepinephrine and adrenaline) can express genotoxic effects in some test-systems. It is interesting that all above mentioned hormones have a phenolic group. Data on possible genotoxic effects of peptide and protein hormones are very scarce, but based on the available literature it is considered that this group of hormones probably lacks mutagenic activities. The possibility that hormones, as endogenous substances, express mutagenic activities results from the fact that DNA is, regardless of chemical and metabolic stability susceptible, to a certain extent, to changeability compatible with the processes of the biological evolution.

Često se polazi od shvatanja da jedinjenja koja su normalno prisutna u biološkim sistemima nemaju genotoksične i mutagene efekte, tako da je mali broj endogenih supstanci testiran na mutagenost. Epidemiološke i eksperimentalne analize ukazale su, međutim, da seksualni steroidi mogu da doprinesu nastanku i/ili održavanju malignih oboljenja. Podrobnija ispitivanja primenom metoda biohemije, molekularne biologije, citogenetike i drugih disciplina otkrila su da se u osnovi maligne transformacije pod dejstvom hormona ne nalaze samo epigenetički mehanizmi poput stimulacije deobe ćelija, već neki hormoni mogu da ispolje genotoksične efekte kao što su kovalentne modifikacije DNK, oštećenja hromozoma i hromozomske aberacije. U slučaju estrogena, pokazano je da prekomerna hormonska stimulacija vodi ka metaboličkoj konverziji ovih hormona do reaktivnih intermedijera uz nastanak reaktivnih kiseoničnih derivata, tako da se ćelije praktično nalaze u uslovima oksidativnog stresa. Individualna i tkivna osetljivost ka nastanku oštećenja DNK i drugih komponenti ćelije, uglavnom proističe iz razlika u efiksanosti enzimskih i neenzimskih mehanizama odbrane od oksidativnog stresa. Pored steroidnih, tieroidni hormoni i kateholamini (dopamin, noradrenalin i adrenalin) mogu da ispolje genotoksične efekte u nekim test-sistemima. Interesantno je da svi gore navedeni hormoni imaju fenolnu grupu. Podaci o mogućim genotoksičnim efektima peptidnih i proteinskih hormona veoma su oskudni, ali se na osnovu raspoložive literature smatra da ova grupa hormona verovatno nema mutagene efekte. Mogućnost da hromoni kao endogene supstance ispolje mutagene efekte proističe iz toga što je DNK pored hemijske i metaboličke stabilnosti podložna izvesnom stepenu promenljivosti kompatibilnom sa procesima biološke evolucije.