Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

MTHFR gene mutation, methylmalonic acidosis, and exercise.

19 January 2003

It is difficult to understand why a mutation in the gene coding for the enzyme methylenetetrahydrofolate reductase (MTHFR) should be associated with homocysteinaemia let alone an increased risk of cardiovascular and neurological disorders (1) unless there is another cause such as “lactic acidosis” (2). In the first place methionine requirements can easily obtained from a normal diet. In the second place the beneficial effect of folic acid supplements may not be related to folic acid per se but to an additive which inhibits xanthine oxidase (3,4). Consider this and other enzyme abnormalities in a broader metabolic context including the effects of exercise.

The availability of homocysteine appears to be increased in anaerobiosis by the hydrolysis of homocysteine-thiolactone. The accompanying release of adenosine trapped by the homocysteine –thiolactone increases the availability of adenosine for trapping as adenosylhomeocysteine (5,6) and hence for ATP resynthesis and the replenishment of adenine nucleotide pools once oxidative phosphorylation resumes. An increase in availability of homocystine promotes the synthesis of methionine, cysteine and succinyl CoA. Succinyl CoA is also generated from alpha ketoglutatate in the Krebs cycle and from that proprionic acid which is synthesised from other aminioacids and/or from the beta oxidation of fatty acids. The likelihood of succinyl CoA being synthesised from the degradation product of homocysteine, methylmalonyl CoA, depends upon the concentration of methylmalonyl CoA, the concentration of the enzyme methylmalonyl CoA mutase, and the availability of the co-factor adenosylcobalamin. The adenosylcobalamin is synthesised from uroporphyrogen III, which is also the substrate for porphyrin and haeme synthesis, and which in turn is synthesised from succinyl CoA.

In the anaerobiosis induced by haemorrhagic shock myocardial tissue lactate and succinyl CoA increase (7). The increase in succinyl CoA is caused by an impairment of its utilisation as substrate in the Krebs cycle to a degree that must be proportional with the degree of anaerobiosis or dysoxia present (8). Tissue lactate increases not only because of an impairment of mitochondrial oxidative phosphorylation but also because of the catabolism of the cysteine derived from the catabolism of methionine and homocysteine into pyruvate. The rise in blood lactate and accompanying rise in the secretion of lactate into renal tubules appears to impair the secretion of uric acid and may thus limit the rate and degree of adenine nucleotide loss in urine. Hence the potential for an increase in both uric acid and homocysteine in serum whenever the degree of anaerobiosis or dysoxia becomes excessive.

Methylmalonic acidosis may cause the death of neonates and cause neurological and mental disorders and even organ failures in adults. The methylmalonic acidosis is caused by an impairment of the activity of the enzyme methylmalonyl CoA mutase which catalyses the conversion of methylmalonyl CoA into succinyl CoA. The dysfunction may either be reversed by adenosylcobalamin or not. In those in whom it is not reversed by adenosylcobalamin death occurs in infancy. In those in whom the dysfunction is reversed by adenosylcobalamin neurological and mental consequences and even organ failures may develop . The methylmalonic acidosis is almost certainly primarily the product of unreversed ATP hydrolysis induced by a fall in the availability of succinyl CoA not only for the generation of ATP from oxidative phosphorylation synthesis but also for the synthesis of the coenzyme adenosylcobalamin.

Porphyria may also cause neurological and mental diseases, such as that in King George III, abdominal pain and organ failures and death from the organ failures. In these conditions there is an accumulation of aminolevulinic acid (ALA) in the mitochondria because it is not able to pass into the cytosol to form uroporphyrogen III a substrate for adenosylcobalamin synthesis. Thus the conversion of methylmalonyl CoA to succinyl CoA may be impaired and methylmalonic acidosis develop. This impairment of succinyl CoA synthesis is accompanied by an impairment of porphyrin and haem synthesis. The law of mass action dictates that the degradation of homocysteine will also be impaired thus favouring the accumulation of homocysteine its conversion to methionine and the trapping of adenine nucleotides as homocysteione-thiolactone and/or adenosylhomocysteine. Thus hyperhomocysteinemia, hyperuricaemia, and the inappropriate depletion of ATP pools are all favoured in the methylmalonic acidosis caused by impaired function of the enzymes methylmalonyl mutase and those responsible for porphyria.

Patients with the Lesch-Nyman syndrome develop hyperuricaemia, gout, and neurological problems including spacticity, mental retardation and self mutilation. The syndrome is caused by any one of some one hundred abnormalities of the enzyme hyoxanthine-guanine-phosphoribosyl transferase (HGPRTase) which catalyses adenine nucleotide salvage by combining with phosphoribosylpyrophosphate (PRPP) to form IMP and Ppi. On occasions the enzyme defect may reduce activity as much as 98% or even 100%. A relatively benign variant of the syndrome was caused by a change in Km (9). The hyperuricaemia in the Lesch-Nyman syndrome is caused by an excessive production of uric acid induced by the degradation of ATP. Hyperhomocystienaemia may also occur because of the impairment of adenine nucleotide salvage. This syndrome is, therefore, also characterised by an inappropriate depletion of ATP pools and hence of metabolic energy for cellular activities, organ dysfunctions and failures.

If the secretion of uric acid is indeed limited by the secretion of lactate into renal tubules the generation of lactate in severe exercise, both from the Emden-Meyerhoff pathway and from the degradation of the cysteine derived from the homocystiene presumably released from the homocysteine-thiolactone trap, may be one means of preserving adenine nucleotide pools in athletes. The training of athletes is known to increase the efficiency of mitochondrial oxidative phosphorylation (10) as indeed may in ingestion of modest amounts of alcohol (11). From a teleological perspective one would presume that any increase in efficiency of mitochondrial oxidative phosphorylation might be accompanied by an enhancement of the capacity to limit the losses of substrate for ATP resynthesis in urine.

By impairing the conversion of homocysteine into methionine the mutation in the MTHFR gene might cause an increase in homocysteine by impairing its degradation into methionine. On the other hand homocysteine synthesis from endogenous methionine is impaired. A rise in homocysteine levels is, therefore, more likely to occur during anaerobiosis in these patients. In addition to the release of homocysteine from the homocysteine -thiolactone pool homocysteine catabolism into succinyl CoA is impaired in anaerobiosis for the utilisation of succinyl CoA as a substrate in the Krebs cycle is impaired t0o a degree determined by the degree of dysoxia present. The beneficial effects of folic acid, the additive in which is a potent inhibitor of xanthine oxidase, is consistent with this view for xanthine oxidase appears to increase the rate of adenine nucleotide depletion. But xanthine oxidase is only activated under abnormal conditions including hypoxia and cytokine release. That folic acid has a beneficial effect in patients with the mutation in the MTHFR gene implies, therefore, that abnormal conditions prevail and that the increase in homocysteine may indeed be the result rather than the primary or sole cause of the cardiovascular and neurological diseases.

Folic acid rather than its additive might exert a beneficial effect in patients with the mutation in the MTHFR gene by enhancing methionine synthesis and hence the rate at which it is catabolised into homocysteine and succinyl CoA. The increase in availability of succinyl CoA would, in the presence of normal oxidative phosphorylation, tend to enhance the salvage of adenine nucleotide. If, however, anaerobiosis were present pure folic acid could not be expected to enhance ATP resynthesis or limit further the adenine nucleotide in urine. Hence the suggestion that folic acid can only be beneficial in patients who have an anaerobic energy deficit (12). B12, on the other hand could be expected to be of benefit in any patient who had developed a methylmalonic acidosis secondary to competitive inhibition of the conversion of methylmalonyl CoA to succinyl CoA by methylmalonyl Co A mutase by enhancing the synthesis of adenosylcobalamin.

A dietary deficiency in B12 but not in folic acid may cause neurological disorders. The explanation for this may be that a B12 deficiency, but not a folic acid deficiency, may impair the resynthesis of ATP by oxidative phosphorylation by limiting the availability of succinyl CoA in the Krebs cycle and thereby cause a methylmalonic acidosis. The beneficial effect which folic acid supplements have in preventing neurological abnormalities in the newborn may be related to the ability of the additive to inhibit xanthine oxidase and preserve adenine nucleotide stores rather than an enhancement of methionine synthesis from homocysteine. An metabolic energy deficit whatever its causes may indeed be the primary cause of not only neurological disorders but also of psychiatric disorders (13).

The HGPRTase gene is located on the Y chromosome and so the Lesch- Nyman syndrome is confined to males. This is the second of two salvage pathway for adenine nucleotides. That is the combining of adenine and PRPP to form AMP. It is not clear from my readings whether adenosine has to be converted into adenine to accommodate this pathway or whether it can as I have presumed simply diffuse back into cells and recombine with Pi to form AMP and hence ATP. In the absence of the HGPRT gene these must presumably be the sole adenine nucleotide salvage pathways available to women. It would seem, therefore, that men might be better adapted than women to withstanding periodic exposures to severe anaerobiosis such as that occurring with severe exercise. Men who exercise and drink in moderation regularly may owe their protection against cardiovascular and neurological diseases to their sex in addition to an acquired enhancement in their capacity to preserve adenine nucleotide stores and replenish ATP by mitochondrial oxidative phosphorylation (14,15).

1. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis David S Wald, Malcolm Law, and Joan K Morris BMJ 2002; 325: 1202-1206

2. "Lactic acidosis": the common denominator? Richard G Fiddian-Green bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003

3. Spector T, Ferone R. Folic acid does not inactivate xanthine oxidase. J Biol Chem. 1984 Sep 10;259(17):10784-6.

4. Homocysteine, folic acid, uric acid, ATP and free radical scavenging Richard G Fiddian-Green bmj.com/cgi/eletters/325/7374/1202#27955, 19 Dec 2002

5. Homocysteine: an adenine nucleotide trap? Richard G Fiddian-Green (9 January 2003)

6. pH/calcium regulation of homocysteine metabolism Richard G Fiddian- Green (10 January 2003)

7. Kline JA, Thornton LR, Lopaschuk GD, Barbee RW, Watts JA. Lactate improves cardiac efficiency after hemorrhagic shock. Shock. 2000 Aug;14(2):215-21.

8. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid- base balance. Br J Anaesth. 1995 May;74(5):591-606. Review.

9. Sorenson L, Benke PJ. Biochemical evidence of a distinct type of primary gout. Nature 313:1122 n1967.

10. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002 Dec;16(14):1879-86

11. Piquet MA, Nogueira V, Devin A, Sibille B, Filippi C, Fontaine E, Roulet M, Rigoulet M, Leverve XM. Chronic ethanol ingestion increases efficiency of oxidative phosphorylation in rat liver mitochondria. FEBS Lett. 2000 Feb 25;468(2-3):239-42.

12. Homocysteine causes mitochondrial dysfunction Richard G Fiddian-Green bmj.com/cgi/eletters/325/7374/1202#27538, 2 Dec 2002

13. Madness, hyperhomocysteinemia, metabolic rate and body temperature Richard G Fiddian-Green bmj.com/cgi/eletters/325/7378/1433#28469, 6 Jan 2003

14. Tiger L. Nunc est bibendum. Wall Street Journal Europe, January 13, 2003

15. Do port and red wine preserve ATP stores? Richard G Fiddian-Green bmj.com/cgi/eletters/325/7374/1202#27887, 16 Dec 2002

16. Exercise and plasma homocysteine Harpal S Randeva, Vivian Fonseca, Professor, Medicine and Pharmacol, Tulane University, USA; Gordana M Prelevic, Senior Lecturer, Reproductive Endocrinology, Royal Free&UCL, UK (20 December 2002)

Competing interests:   None declared

Competing interests: None declared

Richard G Fiddian-Green, None

None

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