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Catecholamines (CAs; dopamine, noradrenaline, and adrenaline) are biogenic amines that possess 3,4-dihydoroxyphenyl (catechol) nucleus. Three CAs are neurotransmitters in CA neurons in the brain. Dopamine and noradrenaline in the brain regulate a wide range of higher brain functions such as movement, motivation, reward expectation, emotion, and memory. Noradrenaline as neurotransmitter in the peripheral sympathetic nerves and adrenaline as hormone in the adrenal medulla play fundamental roles in physical and mental stress reactions that affect metabolism in all organs. Thus, CAs are related to a wide range of central and peripheral pathology such as Parkinson's disease, schizophrenia, depression, and cardiovascular and metabolic diseases. In 1964 in National Institutes of Health (NIH) tyrosine hydroxylase (TH) was discovered as the first and regulatory enzyme of CA biosynthesis from tyrosine. TH requires tetrahydrobiopterin (BH4), a biofactor that is synthesized from GTP in CA cells as a cofactor. BH4 relates to various physiological and pathological functions regulated by CAs. We have elucidated the properties and the genes of all human CA- and BH4-related enzymes and their roles in physiology and pathology, especially in Parkinson's disease (PD), based on studies on postmortem brains, genetically-modified mice, and familial PD cases. Especially, the relation of CA-related enzymes and BH4 with PD has been discussed in this review.

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Vitamin C (VC), that is, L-ascorbic acid (AsA), is known to be an antioxidant and a cofactor for several hydroxylases. Humans, other primates, and guinea pigs cannot synthesize VC, but rats and other mammals can synthesize this vitamin in liver. Firstly, we demonstrated that the ingestion of various types of xenobiotics increased the hepatic biosynthesis of AsA in rats, leading to marked elevations of urinary and tissue AsA concentrations. It was clarified that stimulation of UDP-glucuronosyl transferase gene expression contributed to the increase in AsA biosynthesis caused by xenobiotics. Secondly, we investigated the functions of VC relating to disease prevention in ODS rats unable to synthesize AsA due to the hereditary lack of L-gulono-γ-lactone oxidase that is the last step enzyme in AsA biosynthesis. VC deficiency decreased the hepatic cytochrome P450 (CYP) in ODS rats, and simultaneously increased the hepatic expression of heme oxygenase-1, which is the rate limiting enzyme of heme degradation. These findings suggested that the hepatic CYP was decreased due to the enhancement of heme degradation caused by VC deficiency. We also found that VC deficiency elevated serum cholesterol concentration due to the suppression of bile acid synthesis. In addition, we reported for the first time that, in the liver of VC-deficient ODS rats, the expression of acute phase proteins and inflammation-related proteins was stimulated in the early stage of VC deficiency, and that VC deficiency elevated serum concentrations of inflammatory cytokines (interleukin-6 and interleukin-1β). Moreover, we established a novel spontaneously hypertensive rat unable to synthesize AsA and observed that this rat required VC for maintaining the blood pressure. The above-described results on the regulation of AsA biosynthesis by xenobiotics in rats and VC functions relating to disease prevention in ODS rats have been discussed in this review.

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