The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
proline hydroxylase, lysine hydroxlyase, procollagen-proline 2-oxoglutarate 3-dioxygenase, trimethyllysine 2-oxoglutarate dioxygenase, dopamine b-monooxygenase, and peptidyl glycine a-amidating monooxygenase (Levine & Hartzell, 1987). Also, many genes are affected (modulated) by ascorbic acid. Genes that are modulated by ascorbic acid include: procollagen, acetylcholine receptor a, pro-atrial natriuretic factor, cytochrome P450’s CYP2A1 and CYP2B1, alkaline phosphatase, osteocalcin, osteopontin, lipid-binding protein, lipoprotein lipase, myosin light-chain 2, and myogenin (Hitomi & Tsukagoshi, 1996).
The vast majority of animals can synthesize vitamin C. D-glucose is the starting molecule. Glucose is metabolized through the pentose phosphate cycle, shunting over to aldonolactonase and l-gulono-gamma-lactone oxidase to produce ascorbic acid (Nishikimi & Yagi, 1996). Primates (including humans), guinea pigs, and some bats and birds do not have the enzyme gulonolactone oxidase, and thus cannot synthesize vitamin C (Banhegyi et al., 1997). The prevailing theory of why the above animals lost the ability to synthesize vitamin C is that all of these animals lived in an ascorbate-rich plant environment for millions of years, and thus lost the gene to synthesize vitamin C due to its uselessness (Cameron & Pauling, 1993). Genetic analysis indicates that the ability to synthesize vitamin C was lost in primates roughly 45-50 million years ago (Nishikimi & Yagi, 1996). Interestingly, this happened very early in the evolution and divergence of primates, long before any primate resembling a human appeared.
A conservative estimate for bodily vitamin C is “a total pool size of about 1500 mg” (Kallner, 1987, p. 422); a more liberal estimate is 5000 mg (Ginter, 1980). Adults lose 3-4% of their total vitamin C daily (Goodman et al., 1996). “An 8-ounce glass of fresh-squeezed orange juice supplies 124 mg of vitamin C” (Reader’s Digest Association, 1999, p. 379). In a non-stressed person, about 200 milligrams per day is needed to maintain vitamin C levels (Lieberman & Bruning, 1997). Absorption of up to 180 mg of vitamin C is 80-90% efficient (Koenig & Elmadfa, 1996). Regular vitamin C supplementation raises blood concentrations of the vitamin by an average of 25-30%. Both dietary and supplemental vitamin C appears to have identical biological effects in maintaining blood levels (Boeing & Rausch, 1996). Vitamin C supplementation of 2000 mg/day raises plasma levels by 57% (Johnston, 1996).
The vitamin C concentration in the brains of different mammals is directly proportional to neuron density (Rice, 2000). In the brain, extracellular vitamin C concentration rises rapidly after behavioral activation (Katsuki, 1996). Vitamin C is transported into non-CNS cells via a sodium-dependent co-transport mechanism (Rose, 1998). Vitamin C in the ascorbic acid form cannot enter the brain; it first must be oxidized to dehydroascorbate to cross the blood-brain barrier (Agus et al., 1997), where it is then reduced back to ascorbate. Oxidized vitamin C is usually regenerated by a very small peptide called glutathione (Banhegyi et al., 1997), and vitamin C can also regenerate oxidized glutathione (Jacob, 1996), depending on which antioxidant molecule is needed most at the time. The enzyme thioredoxin reductase can also recycle vitamin C (May, 2002), as can the antioxidant alpha-Lipoic acid (Xu & Wells, 1996).
Literature Review:
Histamine plays both a varied and powerful role in the brain. Histamine alone can inhibit release of all major neurotransmitters: serotonin, glutamate, acetylcholine, GABA, dopamine, and norepinephrine (Brown, Stevens, & Haas, 2001). Even low levels of histamine can inhibit neuronal firing of all serotonergic receptor subtypes (Lakoski & Aghajanian, 1983). Interestingly, histamine can also release norepinephrine from brain tissue (Bugajski, 1984), in addition to inhibiting its release, as mentioned above. Excess norephinephrine release may lead to anxiety disorders or mania. Histamine administration in rats decreased blood dopamine concentration (Willems et al., 1999). In contrast, histamine administration into anesthetized rat brain raised extracellular dopamine levels (Galosi et al., 2001). Elevated dopamine levels are thought to be associated with psychosis, since classical antipsychotics block dopamine receptors (Victor & Ropper, 2001). Histamine can enhance glutamate signaling (Galosi et al., 2001); excess glutamate signaling can be neurotoxic.
Histamine itself is a very toxic molecule. Even low doses of histamine can kill endothelial cells in culture (Fernandez-Novoa, & Cacabelos, 2001). High histamine levels, known as histaminemia, “causes separation of vascular endothelial cells” (Clemetson, 1999, p. 1). This can lead to heart disease and death. In humans, histamine increases heart rate and lowers blood