Ascorbic Acid in Xenobiotic and Cholesterol Metabolism

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A number of xenobiotics - such as polychlorinated biphenyls, DDT, and aminopyrine - increase the urinary excretion and tissue concentrations of ascorbate in rats, and increase the incorporation of label from [14C]glucose into ascorbate. The rate of ascorbate turnover can increase 5- to 10-fold under these conditions. Although this might be interpreted as suggesting a role for ascorbate in the metabolism of these compounds, it is more likely that it is a response to increased requirement for uridine diphosphate (UDP)-glucuronic acid for conjugation. The effect of the xenobiotics is to increase the activity of hepatic UDP-glucose dehydrogenase activity, withno change in gulonolactone oxidase. The same compounds also increase UDP-glucose dehydrogenase activity in the guinea pig. The increased formation of ascorbate is thus a result of increased availability of glucuronic acid; in rats, this excess glucuronic acid can then be catabolized by way of ascorbate, as shown in Figure 13.2 (Horio andYoshida, 1982).

There is impairment of drug metabolism in ascorbate-deficient guineapigs, which is normalized on repletion (Zannoni et al., 1972), possibly reflecting the effects of ascorbate on expression of cytochrome P450 (Mori et al., 1997). This may also account for the hypercholesterolemia and impaired synthesis of bile acids that is seen in vitamin C-deficient guinea pigs. Cholesterol 7-hydroxylase, the first enzyme of bile acid synthesis, is cytochrome P450-dependent, and its activity is reduced in deficiency.


Although there is no specific site of vitamin C storage in the body, signs of deficiency do not developuntil previously adequately nourished subjects have been deprived of the vitamin for 4 to 6 months, by which time plasma and tissue concentrations have fallen considerably.

The term scurvy is derived from the Italian scorbutico, meaning an irritable, neurotic, discontented, whining, and cranky person. The deficiency disease is certainly associated with listlessness and general malaise, and sometimes changes in personality and psychomotor performance and a lowering of the general level of arousal. The behavioral effects can presumably be attributed to impaired synthesis of catecholamines as a result of reduced activity of dopamine f-hydroxylase (Section 13.3.1).

Most of the other clinical signs of scurvy can be accounted for by effects of deficiency on collagen synthesis as a result of impaired proline and lysine hydroxylase activity (Section 13.3.3).

In general, the effects on collagen synthesis are more marked and more important than those of decreased formation of carnitine (as a result of impaired activity of trimethyllysine and y-butyrobetaine hydroxylases; Section 14.1.1), impaired xenobiotic metabolism, or hypercholesterolemia (Section 13.3.8). However, depletion of muscle carnitine may account for the lassitude and fatigue that precede clinical signs of scurvy.

The earliest signs of scurvy in volunteers maintained on a vitamin C-free diet are skin changes, beginning with plugging of hair follicles by horny material, followed by enlargement of the hyperkeratotic follicles and petechial hemorrhage, with significant extravasation of red cells - presumably the result of increased fragility of blood capillaries from impaired collagen synthesis (Chatterjee, 1978).

Vascular fragility may also result from reduced sulfation of proteoglycans in connective tissue, as may also occur in hyperhomocysteinemia (Section Dehydroascorbate catalyzes the oxidation of homocysteine to ho-mocysteic acid, which is the precursor of PAPS, the sulfate donor for sulfation reactions (McCully, 1971).

At a later stage in deficiency, there is also hemorrhage of the gums, beginning in the interdental papillae, and progressing to generalized sponginess and bleeding of the gums. This is frequently accompanied by secondary bacterial infection and considerable withdrawal of the gum from the necks of the teeth. As the condition progresses, there is loss of dental cement, and the teeth become loose in the alveolar bone, and may be lost.

Wounds show only superficial healing in scurvy, with little or no formation of (collagen-rich) scar tissue, so that healing is delayed and wounds can readily be reopened. The scorbutic scar tissue has only about half the tensile strength of that normally formed.

Advanced scurvy is accompanied by intense pain in the bones, which can be attributed to changes in bone mineralization and demineralization as a result of abnormal collagen synthesis. Bone formation ceases and the existing bone becomes rarefied, so that the bones fracture with minimal trauma.

Some scorbutic patients develop chest pains, and acute cardiac emergency in response to exercise has been reported in some studies. Postmortem examination of patients and experimental animals shows thickening of the pericardium and accumulation of fluid in the pericardial cavity. Thrombosis may also occur, presumably because of hyperhomocysteinemia (Section, and hypercholesterolemia (Section 13.4.8) may also be a factor.

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