The consumption of red meat is probably carcinogenic to humans and is associated with an increased risk to develop
colorectal cancer (CRC). Red meat contains high amounts of
heme iron, which is thought to play a causal role in
tumor formation. In this study, we investigated the genotoxic and cytotoxic effects of
heme iron (i.e.,
hemin) versus inorganic
iron in human colonic epithelial cells (
HCEC), human CRC cell lines and murine intestinal organoids.
Hemin catalyzed the formation of
reactive oxygen species (ROS) and induced oxidative DNA damage as well as
DNA strand breaks in both
HCEC and CRC cells. In contrast, inorganic
iron hardly affected ROS levels and only slightly increased DNA damage.
Hemin, but not inorganic
iron, caused cell death and reduced cell viability. This occurred preferentially in non-malignant
HCEC, which was corroborated in intestinal organoids. Both
hemin and inorganic
iron were taken up into
HCEC and CRC cells, however with differential kinetics and efficiency.
Hemin caused stabilization and nuclear translocation of Nrf2, which induced
heme oxygenase-1 (HO-1) and
ferritin heavy chain (FtH). This was not observed after inorganic
iron treatment. Chemical inhibition or genetic knockdown of HO-1 potentiated
hemin-triggered ROS generation and oxidative DNA damage preferentially in
HCEC. Furthermore, HO-1 abrogation strongly augmented the cytotoxic effects of
hemin in
HCEC, revealing its pivotal function in colonocytes and highlighting the toxicity of free intracellular
heme iron. Taken together, this study demonstrated that
hemin, but not inorganic
iron, induces ROS and DNA damage, resulting in a preferential cytotoxicity in non-malignant intestinal epithelial cells. Importantly, HO-1 conferred protection against the detrimental effects of
hemin.