We all come to the Crossroads of HIF-1alpha and the transsulfuration pathway every single day. Will your flight from the lion end in sulfate or sulfite?
S-Sulfocysteine Helps Us Escape the Lion
One way to think of S-sulfocysteine (SSC), the combination of sulfite and cystine in the blood, is that it is a chemical that helps us escape a lion. Of course, none of us are escaping actual lions right now. However, we do have modern-day lions that induce the HIF-1alpha pathway which are listed to the right.
Even stressful moments in time, such as loss of a loved one, loss of a job, a divorce, or a massive unexpected bill, can lead to increases in adrenaline and norepinephrine that encourage unhealthy gut bacteria to grow. These unhealth bacteria lead to bacterial toxins and leaky gut that induce the HIF-1alpha pathway and CDO with resulting production of sulfite. So even that stressful moment in life can lead to an uptick in sulfite production. We then make SSC to fight the threat, the lion called, STRESS.
Some of the “lions” listed above aren’t related to hypoxia, but the hypoxia pathway is induced by circumstances outside of low oxygen. For the sake of simplicity, let’s use low oxygen and running from a lion as an example. While running from a lion, oxygen is used up quickly. When oxygen goes low in a cell it induces the HIF-1alpha pathway which increases CDO activity. This results in more production of sulfite and more SSC. SSC then fires up NMDA receptors in the central and peripheral nervous system which gives a sense of alertness, allowing us to perceive if any more lions are hiding in the bushes ahead of us. This HIF-1alpha pathway also increases the total amount of blood vessels in the muscles so that the next time the lion attacks, more oxygen will be available to those tissues so that if the escape ever turns into a long-distance sprint, our muscles will be ready.
HIF-1alpha increases CDO activity but it also changes metabolism so that a person makes energy quickly from glucose which comes from carbohydrates (bread, cereal, rice, pasta, fruit, and vegetables). It also helps send glucose through a pathway called the pentose phosphate shunt that makes NADPH. NADPH helps recycle glutathione, a master antioxidant, from its used-up state (oxidized) to its fresh state (reduced). This reduced glutathione can mop up oxidative stress that is happening. This change in metabolism can happen in any cell, including immune cells to give them energy to fight infections. Unfortunately, excess sulfite can inhibit the enzyme that starts the pentose phosphate shunt, glucose-6-phosphate dehydrogenase causing low levels of NADPH. Sulfite can also bind to oxidized glutathione and make recycling of it impossible. Excess sulfite, however, should be metabolized to sulfate, by the end-game enzyme, sulfite oxidase.
The HIF-1alpha pathway’s increase of CDO may lead to more taurine if adequate vitamin B6 is available, but keep in mind that sulfite toxicity can cause a functional B6 deficiency. However, in sulfite toxicity, taurine may be produced from the breakdown of Coenzyme A. Taurine levels are typically high during sulfite toxicity. Taurine acts as a natural antioxidant in the body but is problematic for people suffering from sulfite toxicity. Taurine can help mop up oxidative stress in the synapses in the brain, which is good, but can lead to increased neurotransmitter activity, which can be problematic in people with high SSC levels. Individuals with too much SSC have overactivation of NMDA receptors. Taurine can help with oxidative stress in the brain but may cause a rebound excitatory response after taking taurine. In genetic SUOX/MoCo deficiency, high taurine levels do not appear to be able to prevent neurological damage.
As mentioned above, if done well, the intersection of HIF-1alpha and the transsulfuration pathway helps to increase the total amount of sulfate available. This is if the enzyme that helps to make sulfate, sulfate oxidase (SUOX) is working well. SUOX is the end-game enzyme needed to prevent a feed-forward cycle that keeps the HIF-1alpha pathway turned on as both SSC and sulfite will induce the HIF-1alpha pathway which is explained in more detail in the summary of the MoCo Steal Leads to a Sulfite Paradox. Unfortunately, someone with acquired or genetic SUOX deficiency doesn’t make sulfate in this pathway. Instead, they have a build-up of sulfite, thiosulfate, and SSC. The damaging effects of these compounds are summarized surrounding the silhouette of the human above.
I’m a dietitian, not a physician. Please consult with your provider before making any changes to your diet, supplements, medications or lifestyle. -Meredith Arthur, MS, RD, LD