Vitamin C and sodium valproate

… hSVCT1 (Sodium Vitamin C Transporter 1) expression and function were significantly decreased in intestinal epithelial cells by the histone deacetylase inhibitors (in Australia - Vorinostat - Zolinza), valproic acid, and sodium butyrate (NaB) is part of a comment from a recent abstract (https://doi.org/10.1016/j.jnutbio.2021.108838). Effectively this means sodium valproate decreases vitamin C absorption.

Vitamin C (VC)

As we are unable to produce it ourselves vitamin C is deemed an essential nutrient and as such has four main functions including -

1. Co-factor in various enzymes – including collagen synthesis, carnitine synthesis, catecholamine synthesis, cholesterol synthesis, synthesis of several hormones, neuropeptide amidation and release in the brain, tyrosine metabolism;
2. Antioxidant – regenerate α-tocopherol and CoQ10, effective scavenger of free radicals and other reactive oxygen and nitrogen species under physiological conditions ie protective against oxidative stress – refer Note 1. The brain utilizes 25% total body glucose which means high oxidative metabolism that necessitates protective antioxidants; the brain preferentially retains VC at the expense of all other tissues. Neurodegeneration occurs when there is sustained high oxidative stress such that all available VC in the brain is consumed, resulting in none being available C to modulate neuronal metabolism.
3. Pro-oxidant – may increase Reactive Oxygen Species (ROS) in cells via dihydrogen peroxide. Vitamin C's pro-oxidant activity leads to the breakage of cellular DNA that interrupts the redox balance and eventually alters cellular metabolism such as energy metabolism through NAD depletion.
4. Other – changes ferric to ferrous and thus increases iron absorption in the duodenum, down-regulates HIF 1α (associated with low oxygen environments), recycles α-tocopherol in the lipid bilayers and in erythrocytes, prevents glutamate-induced cell damage and death, and other functions.

Transporters

Vitamin C's three main transporters include -

1. SVCT1 – sodium vitamin C transporter 1

• tissue distribution - apical brush border membranes of the intestines, renal tubular cells, liver, lungs and skin,
• primary functions are to enhance intestinal absorption and renal reabsorption of VC and to regulate intestinal VC uptake. Megadoses of vitamin C (> 1 g) are less effective than 250-500 mg doses several times per day;

2. SVCT 2 – sodium vitamin C transporter 2 

• tissue distribution - found in most other tissues, and especially brain, placenta, retina, bone,
• primary functions are to transport VC from cytosol into the mitochondrial matrix, preserve intracellular VC status, and to regulate VC uptake and neuronal content; not present in astrocytes however oxidative stress can induce SVCT2 in astrocytes and increase their expression in neurons,
• is a Ca(2+)/Mg(2+)-dependent transporter ie when Ca²⁺ and Mg²⁺ are absent, the SVCT2 transport system is in an inactive form (refer Note 2),
• expression inhibited by TNF-α and IL-1β which suggest SVCT2 may be regulated by the inflammatory response; TNF-α is elevated in the presence of low B12.

3. GLUT – primarily transports glucose into cells

• Glut 1 + Glut 3 transport DHA (dehydroascorbic acid) into neurons and glial cells. This route is plan B for increasing vitamin C in neurons.

Bioavailability

The main factors that affect vitamin C's bioavailability are the absorption rate at the intestinal level and renal re-absorption rate. Inadequate vitamin C status manifests as -

• classic - impaired wound healing, gingivitis, perifollicular haemorrhages, ecchymoses, petechiae, eg scurvy,
• non-classic - malaise, fatigue and lethargy – may be partially due to reduced levels of carnitine and reduced synthesis of epinephrine.

Carnitine

One of the mechanisms by which sodium valproate decreases carnitine availability is inhibition of endogenous carnitine production. Sodium valproate’s inhibition of vitamin C absorption is one of the likely mechanisms as insufficient vitamin C means the body cannot produce adequate carnitine.

There are some populations that are at particular risk of carnitine deficiency due to sodium valproate-induced vitamin C inadequacy, including –

• Vegans - the primary source of carnitine is from the conversion of lysine to carnitine. Vitamin C is essential in this process and sodium valproate reduces its availability. Both carnitine and vitamin C interventions are probably advisable.
• Limited animal food intake – as the animal food intake reduces so the dependency on the production of carnitine from the lysine + vitamin C pathway increases; reduced vitamin C availability means a likely limited production of carnitine that may not meet body requirements.
• Enteral + parenteral feeds - do these formulas contain adequate vitamin C to compensate for its reduced uptake induced by sodium valproate? Further do these formulas contain adequate carnitine?

Clinical Questions

What interventions will you initiate when sodium valproate is prescribed -will you –

• request vitamin C status and magnesium levels be clarified?
• recommend prophylactic vitamin C and magnesium interventions?
• ensure vitamin C and magnesium interventions are administered at a different time from sodium valproate?
• check that other prescribed medications do not also negatively impact vitamin C status and magnesium levels?
• ensure the maximum individual dose for the vitamin C intervention is not more than 500 mg?

Conclusions

The negative impact of sodium valproate on nutritional factors is significant and has ongoing consequences for the consumer, particularly those who do not consume animal foods or only consume them in very limited quantities. The inclusion of vitamin C, magnesium and carnitine in management strategies has the dual benefits of reducing side effects and improving outcomes for the consumer.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Pharmaconutritional Consequences

Medications That May Adversely Affect Nutritional Status

Biochemistry

Recent relevant biochemistry indicates -

• elevated cholesterol – may be advisable to consider a drug intervention.

Pharmaconutrition

Dietary levels of caffeine intake in conjunction with drug inhibit antinocieception

Concurrent ingestion of paracetamol and iron resulted in increased rate of iron absorption and decreased extent of drug absorption. There is a recommendation that paracetamol and iron be administered at different times from each other.

Observations

Mr ABA is a tall, well-built, slender, pleasant, polite man who was holding the door open for the residents whilst doing his daily lap around the building - he looks good.

Mr ABA is a resident because another family member is also a resident in the same facility and there is no-one else to care for him.

What else would you include?

Please read this as it is important …

The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.