This article is not medical or healthcare advice. Before starting and health or medical related regimen seek the advice your Primary Care Physician, or an M.D.
One of the most used terms in the chronic illness community, is 'herx reactions', but it is often used as a catch all term for any adverse events that happen, especially during detox protocols, especially mold related toxicity. This article is intended to shed some light on the mechanics of what happens, and why.
MRP2 - ABCC2 Gene
ABCC2, encodes for multidrug resistance protein 2 (MRP2), is a critical component of detoxification and drug metabolism by transporting phase II metabolites. MRP2 is expressed in the canalicular of hepatocytes, and functions in biliary transport. This protein also transports bilirubin out of liver cells, and into bile. Said simply, one of its main jobs is to chaperone toxins through the liver. The body will protect this protein at almost all costs and go to great lengths to do so given its importance in the detoxification of harmful compounds. Toxins make their way through the phase 1 system (CYP450 set of enzymes) to become water solluable, they next go through phase 2 detoxification depending on their molecular make up. After phase 2 detoxification they are escorted by MRP2 towards the Bile Salt Export Pump (ABCB11). During this process, if the liver gets over loaded with toxins, the liver secludes the MRP2 proteins to protect them.
Bile Salt Export Pump (Phase 2.5 / 3) - ABCB11 Gene
Next, during this process, the Bile Salt Export Pump (a valve that leads from the liver to the gall bladder) closes, and the toxins are instead shunted to another exit door out of the liver and into the blood stream. Now that the toxins are in the blood stream with the bile, four main symptomologies and impacts occur. First, the bile and bile alts are excreted through the skin - resulting in itching, hives, rashes at times. Second, the toxins hit the kidneys, and can result in kidney stress, low back pain and tightness. Third, the toxins hit the brain, crossing the blood brain barrier resulting in cognitive issues - headaches, confusion, brain fog, etc. And lastly, the lymph system is often overloaded by all the toxins circulating in the blood, and lymph nodes become swollen during this process. The BSEP can also become closed under high estrogen conditions. Additionally aggressive use of agents that promote Phase 1 detoxification pathways can overload the Phase 2 pathways. Aggressive use of binders, can signal to the body to dump and release toxins to the liver which can again overload the livers capacity to handle the toxin load. Other strategies like sauna, or chelating agents which can increase the release of toxins and increase the level of circulating toxins can result in the liver being overloaded. This process is referred to by some as Phase 2.5 or Phase 3 detox.
FXR Receptor - NR1H4 Gene
The NR1H4 gene encodes for the farnesoid X receptor, known as FXR, which is a major bile acid receptor. FXR is a bile acid-activated transcription factor critical for the regulation of bile synthesis, homeostasis, and enterohepatic flow. Specifically, FXR regulates the expression of ABCB11, and suppresses CYP7A1. Ah ha. So, FXR exerts control over the Bile Salt Export Pump! Genetic mutations all along this pathway, ABCC2, ABCB11, and NR1H4 make one susceptible to this process where the BSEP closes down, putting toxins into the blood stream.
Also note that FXR suppresses CYP7A1, one of the key genes that processes cholesterol. FXR, when heavily mutated along with CYP7A1, results in high levels of lipids in the blood, and challenges during detoxification.
Each of these genes, like most in the body require specific nutrient based cofactors to function, and also have specific herbs that can upregulate and downregulate their functioning. Examining the specific genetics in Phase 2.5/3.0 pathways, exploring strategies to mitigate the potential of the BSEP closing and avoiding some of the common symptomologies associated with overly aggressive detoxification, can be helpful during detoxification programs to avoid 'herxing'.
Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis
Significance and Mechanism of CYP7a1 Gene Regulation during the Acute Phase of Liver Regeneration. by Lisheng Zhang, Xiongfei Huang, et. al. Molecular Endocrinology, Volume 23, Issue 2, 1 February 2009, Pages 137–145, https://doi.org/10.1210/me.2008-0198
Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid
Lipid-Regulating Effect of Traditional ChineseMedicine: Mechanisms of Actions