Phase II Methyltransferase Detoxification Enzymes and Methylation Capacity
A cell’s methylation capacity is defined as the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). A ratio of less than four indicates an impaired methylation capacity, which could result from a decrease in SAM level (universal methyl donor) or an elevated SAH, a potent methyltransferase inhibitor. An increase in SAH level is detrimental to methylation pathway as it inhibits methyltransferases involved in methylation, and methyltransferases involved in phase II enzyme and creatine synthesis (e.g. COMT and GAMT), among others. Figure 1 lists all vital nutrients required to maintain a healthy methylation. Deficiency in any of these key nutrients would affect methylation capacity and hence ability to provide methyl group to phase II methyltransferases affecting toxin removal, estrogen detox, and creatine synthesis.
Having this, it is prudent for patients with impaired methylation capacity to first improve their SAM:SAH ratio before introducing any detoxification programs. Lowering homocysteine may not be enough to restore methylation capacity. Patients should ensure that the SAM:SAH ratio is within the reference range, not only homocysteine. Many patients have healthy homocysteine levels while also having impaired SAM:SAH ratios (impaired methylation capacity). Patients with SNPs in methylation pathway enzymes should not be discouraged from enrolling in detoxification regimens. Genes do not tell functional methylation capacity. Just because a patient has a SNP that might predispose them to a deficiency in methylation, does not mean they actually have impaired methylation. In fact, they could have completely normal methylation.
Creatine and Methylation Capacity
Creatine in the form of creatine phosphate plays an important role in ATP regeneration (Fig.1). The human body excretes about two grams of creatine in the form of creatinine via urine daily. Humans replenish creatine stores via diet or de novo synthesis from glycine and arginine. Creatine is mainly found in red meat (muscle); it is scarce in other types of meat and is largely absent in plants. Vegans and vegetarians rely on de novo synthesis of creatine and place high demand for glycine, arginine, and SAM (methyl donor for GAMT enzyme, the key enzyme in creatine synthesis). It is estimated that 75 percent of SAH produced in the human body is from GAMT activity. Studies showed that vegans and vegetarians tend to have higher homocysteine levels than the general population and hence elevated SAH.
Glycine is the amino acid that is most frequently conjugated to toxins in humans. Glycine is also in high demand for creatine synthesis in vegetarians, vegans, and omnivores with low intake of red meat (creatine level is low in chicken and fish and is not enough to replenish creatine stores). During detoxification regimens, toxins stored in fat tissues are mobilized and activated by cytochrome P450 (CYP450) enzymes to intermediate substances, and hence the demand for glycine by phase II enzymes increases.
With poor nutrition, the supply of creatine and glycine from the diet may be inadequate. This may quickly lead to depletion of glycine reserves. Glycine would be required for de novo creatine synthesis and toxin conjugation (the demand for both pathways increases during detoxification). For every toxin removed, a molecule of glycine is lost forever from the body. This situation is more problematic in patients with elevated SAH, as increases in GAMT activity requires replenishment of creatine reserves. Poor creatine in diet would further increase SAH levels, exacerbating methyltransferase inhibition and impairing toxin and estrogen detoxification. It is prudent for omnivores to cut down on red meat consumption but not to eliminate red meat from their diet during detoxification. Vegans and vegetarians should be extra careful to consume a proper diet rich in glycine, arginine, cysteine, and key vitamins and minerals essential for methylation support especially vitamin B12 (see Fig. 1).