The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
Inagaki, Yamatodani, & Watanabe, 1991).
One of the main ways that the brain communicates with the rest of the body is via the hypothalamic-pituitary-adrenal (HPA) axis. Within this axis of activity, the nervous system (brain) regulates the body’s endocrine (hormone) system, and vice-versa. The immune system also interacts with the HPA axis to a certain extent. This axis is the major regulator of virtually all bodily activity. Many different types of stress can raise the levels of one of the most important HPA axis hormones, the peptide corticotropin-releasing hormone (CRH) (Koob, 1999). CRH then stimulates secretion of adrenocorticotropic hormone (ACTH). ACTH then stimulates secretion of a class of steroid hormones called glucocorticoids (Axelrod & Reisine, 1984), of which cortisol is the most important. Later, after the stressor is gone, there is a negative feedback loop that returns the HPA axis to normal activity. However, when the HPA axis is overstimulated for prolonged periods due to chronic stress, the negative feedback loop fails (Johnson et al., 1992). Glucocorticoids can have both positive and negative effects. They have anti-inflammatory actions (Lewin, 1994), but they can also suppress proper immune function. As will be mentioned later, histamine plays a role in HPA axis stimulation.
Vitamin C has a very interesting history. Over two hundred years ago it was realized that certain fruits could help prevent a connective tissue wasting disease known as scurvy in ocean-bound sailors. However, the antiscorbutric factor in the fruits (such as lemons and limes), was not identified until the 20th Century. It was then that Vitamin C was isolated in 1928 from adrenal gland by the Nobel prize-winning chemist Albert Szent-Gyorgy, and named ascorbic acid (Grunewald, 1993). It was subsequently isolated from fruit (lemons) in 1932 (Haas, 1992), and shortly thereafter was synthesized in 1933 (Jacob, 1996). Vitamin C is mainly found in fruits and vegetables (Haas, 1992). “The best-known sources of vitamin C are the citrus fruits – oranges, lemons, limes, tangerines, and grapefruits” (Haas, 1992, p. 142). The best vegetable vitamin C sources are black currants and raw red peppers (Reavley, 1998). Vitamin C has been the best selling nutritional supplement for decades; in 1993 its sales were 7 million (Firshein, 1996). It is best used in powdered form (Vayda, 1994). Calcium ascorbate, sodium ascorbate, and ester-C are better tolerated than ascorbic acid (Vayda, 1994), presumably due to their non-acidic chemistry (ascorbic acid sometimes irritates the stomach).
Vitamin C has a molecular weight of 176.1. Its chemical formula is C6H6O8. The chemical name is 2,3-enediol-l-gulonic acid (Koenig, 1996). Vitamin C is an organic chemical known as a ketolactone, and has two dissociable hydrogen atoms. “At physiological pH ascorbate is nearly totally in its anionic form” (Levine & Morita, 1985, p. 5). This molecule that has one dissociated hydrogen atom and one weakly attached hydrogen atom is called ascorbate. Vitamin C analogues that have 100% biological activity include l-dehydroascorbic acid, l-ascorbic acid-6-palmitate, and l-ascorbic acid-5, 6-diacetate (Koenig & Elmadfa, 1996).
Dehydroascorbate differs from ascorbate in that it lacks the two ionizable hydroxyl groups (Rose, 1988). A hydroxyl group contains one oxygen and one hydrogen atom. When both hydrogens have dissociated from their connecting oxygen atoms, the molecule rearranges and the oxygen atoms each gain a double bond with the rest of the dehydroascorbate molecule. Technically, dehydroascorbate is not an acid, since it cannot release any hydrogen atoms into solution. It is relatively hydrophobic compared to ascorbate, and thus can be transported across the fatty cell membranes. Dehydroascorbate has antiscorbutric properties, but not antioxidant properties (Jacob, 1996). When vitamin C is oxidized to dehydroascorbate, it is transported to neighboring cells, and then reduced back to ascorbic acid (Nualart, et. al., 2003).
The main role of vitamin C is to manufacture collagen (Reavley, 1998), via the hydroxylation of the amino acid proline (Grunewald, 1993). It helps produce the oxygen-carrying molecule hemoglobin and also aids in iron absorption (Reader’s Digest Association, 1999). Vitamin C oxidizes lysine to hydroxytrimethyllysine to synthesize the non-essential amino acid carnitine (Goodman et al., 1996). It helps form bones, cartilage, teeth, and strengthens capillaries (Hoffer & Walker, 1978), and this is mainly due to its collagen synthesis role (Hediger, 2002). Vitamin C converts folic acid to folinic acid (Goodman et al., 1996), and hydroxylates the neurotransmitter dopamine to form norepinephrine (Goodman et al., 1996).
Known enzymes dependent on vitamin C for optimal activity include: 4-hydroxyphenyl pyruvate dioxygenase, g-butyro betaine, 2-oxoglutarate 4-dioxygenase,