The Role of Pyridoxal Phosphate in Steroid Hormone Action and Gene Expression

Steroid hormones act by binding to, and activating, nuclear receptors that then bind to hormone response elements on DNA, increasing (or sometimes decreasing) the transcription of specific genes.

Early studies showed that pyridoxal phosphate reacts with a lysine residue in the steroid receptor protein and extracts the steroid-receptor complex from tight nuclear binding. The specificity for pyridoxal phosphate, but not pyridoxal, and the low physiological concentration at which the effect can be observed, led Cidlowski and Thanassi (1981) to propose that pyridoxal phosphate may have a physiological role in the action of steroid hormones. It acts to release the hormone-receptor complex from tight nuclear binding, resulting in release of the steroid from the nucleus, and frees or recycles receptors for further uptake of steroid.

In experimental animals, vitamin B6 deficiency results in increased and prolonged nuclear uptake and retention of steroids and hormones in target tissues, and enhanced end-organ responsiveness to low doses of hormones (Bender, 1987). Allgood and Cidlowski (1992) prepared a variety of gene constructs of marker genes with response elements for estrogens, androgens, glucocorticoids, and progestagens and transfected these into various cell lines in culture. Incubation in a vitamin B6-deficient medium (together with the addition of the antimetabolite 4-deoxypyridoxone) led to a two-fold increase in expression of the reporter gene, whereas addition of a high concentration of pyridoxine led to a halving of gene expression. It thus seems likely that pyridoxal phosphate acts to terminate the nuclear action of steroid hormones.

Later studies showed that the effect of pyridoxal phosphate is mediated by the nuclear transcription factor NF1; gene constructs lacking an NF1 binding site are insensitive to the effects of pyridoxal phosphate deficiency or excess. Pyridoxal phosphate does not only regulate the expression ofhormone-inducible genes, it inactivates the tissue-specific transcription factor for albumin (by forming a Schiff base to an essential lysine residue), and the expression of a variety of housekeeping genes is increased in experimental vitamin B6 deficiency (Oka et al., 1994; Tully et al., 1994; Oka, 2001). Proliferation of both steroid-dependent and steroid-independent cancer cells in culture is reduced by higher than normal concentrations of pyridoxal in the culture medium (Davis and Cowing, 2000).

9.4 VITAMIN Be DEFICIENCY

Gross clinical deficiency of vitamin B6 is extremely rare. The vitamin is widely distributed in foods (although a significant proportion in plant foods may be biologically unavailable; Section 9.1), and intestinal flora synthesize relatively large amounts, at least some of which may be absorbed and hence available.

A variety of studies have shown that 10% to 20% of the population of developed countries have marginal or inadequate status, as assessed by erythrocyte transaminase activation coefficient (Section 9.5.36) or plasma pyridoxal phosphate (Section 9.5.1; Bender, 1989b). This may be sufficient to enhance the responsiveness of target tissues to steroid hormones (Section 9.3.3), and may be important in the induction and subsequent development of hormone-dependent cancer of the breast and prostate. Vitamin B6 supplementation may be a useful adjunct to other therapy in these common cancers; certainly, there is evidence that poor vitamin B6 nutritional status is associated with a poor prognosis in women with breast cancer.

In vitamin B6-deficient experimental animals, there are skin lesions (e.g., acrodynia in the rat) and fissures or ulceration at the corners of the mouth and over the tongue, as well as a number of endocrine abnormalities; defects in the metabolism of tryptophan (Section 9.5.4), methionine (Section 9.5.5), and other amino acids; hypochromic microcytic anemia (the first step of heme biosynthesis is pyridoxal phosphate dependent); changes in leukocyte count and activity; a tendency to epileptiform convulsions; and peripheral nervous system damage resulting in ataxia and sensory neuropathy. There is also impairment of immune responses, as a result of reduced activity of serine hydroxymethyltransferase and hence reduced availability of one-carbon substituted folate for nucleic acid synthesis (Section 10.3.3). Ithas been suggested that the vitamin B6 antagonist deoxypyridoxine may be a useful adjunct to immunosuppressive therapy (Trakatellis et al., 1997).

Much of our knowledge of human vitamin B6 deficiency is derived from an outbreak in the early 1950s, which resulted from an infant milk preparation that had undergone severe heating in manufacture, leading to the formation of pyridoxyllysine by reaction between pyridoxal phosphate and the e-amino groups of lysine in proteins. Pyridoxyllysine has little biological activity, and may also be an antimetabolite of vitamin B6, thus exacerbating the deficiency. In addition to a number of metabolic abnormalities, many of the affected infants convulsed. They responded to the administration of vitamin B6 supplements.

Investigation of the neurochemical basis of the convulsions seen in vitamin B6 deficiency revealed the role of GABA as an inhibitory neurotransmitter; GABA is synthesized by decarboxylation of glutamate (see Figure 6.3). More recent studies have suggested that the accumulation of hydroxykynurenine as a result of impaired activity of kynureninase (see Figure 9.4) may be the critical factor precipitating convulsions, and GABA depletion maybe a necessary but not sufficient condition for convulsions in vitamin B6 deficiency (Guilarte and Wagner, 1987).

The excretion of oxalate is increased in vitamin B6 deficiency because of depressed activity of alanine glyoxylate transaminase, leading to increased accumulation of glyoxylate and onward metabolism to oxalate catalyzed by lactate dehydrogenase. The administration of vitamin B6 supplements has some beneficial effects in reducing oxalate excretion in idiopathic oxalate stone formers, by increasing the activity of glyoxylate transaminase and hence reducing the metabolic burden of oxalate. In primary hyperoxaluria, alanine glyoxylate transaminase either has very low activity or is mistargeted into mitochondria rather than peroxisomes. Again, there is an increased glyoxylate burden, leading to considerably increased synthesis and urinary excretion of oxalate. Some cases of primary hyperoxaluria are vitamin B6 responsive (Section 9.4.3).

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