The exposure of RNA and DNA nucleobases to the oxidant
hypochlorous
acid (HOCl) results in the generation of different stable chlorinated
products. These chlorinated nucleobases are formed in vivo, particularly
in chronic inflammatory pathologies, which are characterized by the
overproduction of HOCl by myeloperoxidase. As such, chlorinated nucleosides
are used as biomarkers of inflammation. However, these compounds have
also attracted attention as potential chemotherapeutic agents with
8-chloro-adenosine (8ClA), for example, currently in clinical trials
for the treatment of hematological cancers, including chronic lymphocytic
leukemia. 8ClA has mainly RNA-directed effects in malignant cells,
with exposure resulting in ATP depletion and apoptotic cell death.
Whether 8ClA has significant reactivity with nonmalignant cells has
not been widely studied. Here we show that prolonged incubation of
J774A.1 macrophage-like cells with 8ClA results in the perturbation
of cellular metabolism and apoptotic cell death. These effects are
associated with an accumulation of 8-chloroadenosine triphosphate
(8Cl-ATP), an effect not seen in experiments utilizing other chlorinated
nucleosides. Exposure of the macrophages to 8ClA did not significantly
change basal mitochondrial respiration or glycolysis but resulted
in an increase in maximal mitochondrial respiration as well as spare
respiratory capacity within these cells. Additionally, 8ClA exposure
also altered the mRNA expression of a range of antioxidant and DNA
damage repair genes in the macrophages in a manner consistent with
a reduction in the capacity of the cells to cope with oxidative stress
and repair DNA damage. Taken together, these results provide new insight
into pathways by which the production of HOCl during chronic inflammation
could perturb immune cell function and may also have implications
for the use of 8ClA as a chemotherapeutic drug.