Standard therapeutic regimens normally include repeated exposure to HBO over several days. It was assumed that repeated exposures may result in an accumulation of DNA damage, which could enhance a possible mutagenic risk. Surprisingly, when healthy human subjects were exposed to repeated HBO exposures, DNA damage was only found after the first treatment but not after or further HBO exposure27, 33. The extent of DNA damage after repeated HBO was even lower than in the control blood sample taken before the first HBO27, 33. Furthermore, the comet assay experiments revealed that a reduced first HBO of shorter exposure (for example 20 min at 1.5 bar) did not induce DNA damage but was sufficient to induce adaptive protection against further HBO-induced DNA damage27, 33. This adaptive effect was demonstrated to be a cellular response which cannot be explained by enhanced repair activity, but seems to be due to enhanced scavenging of oxygen species distant from nuclear DNA or increased sequestration of transition metals27, 33.
The induction of heme oxygenase-1 (HO-1) seems to play a crucial role in the protection against HBO-induced DNA damage: Lymphocytes from healthy volunteers showed a markedly increased HO-1 protein concentration after HBO exposure both in vivo34 and in vitro35, 36. Furthermore, in an in vitro study using cultured V79 - Chinese hamster cells, HO-1 overexpression significantly reduced the HBO-induced DNA damage37, and inhibition of HO-1 with tin-mesoporphyrin aggravated the HBO-related genotoxicity and completely abrogated the adaptive protection against HBO-induced DNA
damage, both in vitro and in vivo35, 38, 39.
The role of another mediator, nitric oxide (NO), the release of which is tightly regulated by HO-1, for HBO-induced DNA damage is less clear: Increased formation of NO per se caused DNA strand breaks no matter whether NO release was a result of administration of NO donors40, 41, 42 or due to cytokine stimulation42, 43. By contrast, increased DNA damage observed in other studies (with patients with hyperlipidemia44 or type I diabetes mellitus45) was not related to the blood nitrate concentrations, e.g. endogenous NO production. Furthermore, NO has both anti- and prooxidant properties depending on the local milieu. In addition, the genotoxic potential of NO is referred to the formation of peroxynitrite from NO and superoxide46' 47 under conditions of increased release of these two molecules, but both increased48 and decreased49 NO production has been reported during HBO exposure. Finally, administration of NO donors leads to the activation of HO-150, which plays a crucial role for the defense against HBO-induced DNA damage as explained above.
Consequently, the effect of the interaction between HBO, NO, and HO-1 on DNA damage was investigated in rats exposed to hyperbaric oxygen39. Increased NO formation due to pretreatment with the NO-donor SIN-10 doubled the HBO-induced DNA single strand breaks. Furthermore, the increased DNA damage affiliated with HO-1 blockade seemed to be independent of endogenous NO production, since blood nitrite and nitrate concentrations, a surrogate for NO production, remained unchanged during HO-1 inhibition. The latter result suggests that the protective effect of HO-1 is related to the formation antioxidant molecules generated by HO-1, e.g. the heme degradation products bilirubin and iron, rather than the regulatory function of HO-1 with respect to NO production.
Interestingly, in contrast to these findings demonstrating that repeated HBO exposures may trigger adaptative mechanisms protecting against further DNA damage, the overall antioxidative capacity of the body decreased after repeated HBO-treatments, most likely due to increasing oxidative stress to the organism.
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