Antioxidants to the Rescue: Restoration of PPOX in Variegate Porphyria

Porphyrias are a class of diseases that arise from dysfunctions in any of the eight steps in heme biosynthesis. Specifically, variegate porphyria (VP) is caused by mutations in protoporphyrinogen oxidase (PPOX), which catalyzes the second-to-last step of this pathway. The decreased PPOX activity results in the accumulation of heme precursors, which have the potential to induce cellular damage by the absorption of UV light and subsequent formation of reactive oxygen species (ROS). However, little work has been done on the state of oxidative stress in patients with VP. Ferrer et al. hypothesized that lymphocytes from VP patients would not only show higher mitochondrial ROS production, but also impaired antioxidant defenses. Therefore, they set out to investigate the influence of VP on the redox state of patients and the impact of dietary supplementation with vitamins E and C.

First, the authors established the redox condition of VP lymphocytes relative to healthy controls. They found that the H2O2 detoxifying enzymes catalase and glutathione peroxidase had decreased activity in VP cells while levels of ascorbate and α-tocopherol did not differ significant. Interestingly, H2O2 production was also similar, except upon stimulation of cells by phorbol myristate acetate, which resulted in greater ROS production in VP cells. Collectively this suggests a state of oxidative stress in VP patients. Next, they investigated the effects of a six-month vitamin E and C supplementation on VP patients. While there was no big impact on ascorbate or α-tocopherol levels, it did produce an increase in activity of glutathione reductase and superoxide dismutase. In addition, treatment restored PPOX mRNA expression in VP lymphocytes to the level exhibited by the healthy control. Therefore, vitamins E and C appear to not only promote the body’s ability to combat ROS, but also restore PPOX activity, which is characteristically decreased in VP.

Figure 1: Expression of PPOX before treatment with vitamins E and C (left) and after. A # denotes statistically significant difference between VP and control.
Figure 1: Expression of PPOX before treatment with vitamins E and C (left) and after. A # denotes statistically significant difference between VP and control.
Figure 2: Expression of catalase before treatment with vitamins E and C (left) and after. A # denotes statistically significant difference between VP and control.
Figure 2: Expression of catalase before treatment with vitamins E and C (left) and after. A # denotes statistically significant difference between VP and control.

This study demonstrates that women with VP are in a state of oxidative stress due to the decreased activity of glutathione peroxidase and catalase, and that supplementation with vitamins E and C can help restore redox balance by increasing superoxide dismutase and glutathione peroxidase activity. However, the most significant result of this study is evidence for the restoration of PPOX mRNA after supplementation. Since low PPOX activity causes the typical symptoms of VP such as photosensitivity and acute attacks of abdominal pain, restoration of this enzyme’s expression is quite significant as it may help to relieve the condition of VP, a cure for which has yet to be found. However, more work needs to be done on the effects this supplementation has on both the photosensitivity and occurrence/severity of abdominal attacks in order to fully assess its potential as a new form of treatment.

Reference: Ferrer, M. D. Tauler, P. Sureda, A. Palacín, C. Tur, J. A. Pons, A. Eur. J. Clin. Invest. 2013, 43, 688-678.

Please visit the Variegate Porphyria page if you would like to read more information on this disease.