June 2004 bmj.com Rapid Responses for Wagner and Groves, 325 (7370) 913-914 http://bmj.bmjjournals.com/cgi/eletters/325/7370/913 Iatrogenic diseases with a common cause? by Richard G Fiddian-Green To what degree might all the chronic diseases,like diabetes, coronary artery disease, hypertension, chronic obstructive pulmonary disease, chronic uveitis, gastro-oesophageal reflux disease, multiple sclerosis, depression, osteoporosis, Parkinson's and Alzheimer's, be different manifestations of a common disorder? That disorder is an impairment of mitochondrial oxidative phosphorylation, be it focal, regional and/or systemic. More importantly, to what extent might these illnesses be the product of ~medications~ taken in preceding decades...that have either induced or compounded the severity of an impairment of mitochondrial oxidative phosphorylation? Somatic mutations of mitochondrial DNA (mtDNA) are implicated in the pathogenesis of cancer, neurological disorders, and multisystemic features such as cardiomyopathy and diabetes mellitus (1). "In man, cells accumulate somatic mutations of mitochondrial DNA (mtDNA) as part of normal ageing. Although the overall concentration of mutant mtDNA is low in tissue as a whole, very high numbers of various mtDNA mutations develop in individual cells within the same person, which causes age-associated mitochondrial dysfunction". When the proportion of mutant mtDNA exceeds a critical threshold concentration, a defect of mitochondrial oxidative phosphorylation results. A combination of different respiratory chain complexes (I, III, IV, and V) can be involved, but complex IV (cytochrome c oxidase, COX) is often affected". An impairment of mitochondrial oxidative phosphorylation appears to be the primary cause of organ dysfunctions and failures, including psychiatric disorders, in the acutely and possibly even in the chronically ill (2-17). The most common causes of impaired mitcohondrial oxidative phosphorylation are an impairment of oxygen and/or nutrient delivery and the many inhibitors or uncouplers of oxidative phosphorylation which may be contained in: . recreational drugs, . medications prescribed and/or . environmental pollutants. The impairment may on occasions be due to increasing the demand for energy from ATP hydrolysis beyond the capacity of mitochondria to replenish their ATP stores. Impaired mitochondrial phosphorylation generates AMP from ATP. AMP is the substrate for free radical generation. Free radicals may induce somatic mutatations in DNA, and are the probable cause of the mutant mtDNA found in association with ageing and the chronic diseases associated with ageing (18,19). Of particular concern is the ~mixing~ of drugs commonly prescribed to and taken by the elderly, including analgesics, antidepressants, statins, and beta blockers, all of which have the potential to impair in different ways the adequacy of mitochondrial oxidative phosphorylation. Given the frequency with which and duration for which these medications are prescribed for both organic and "functional" diseases, such as the irritable bowel syndrome, the possibility that they might even enhance the aging process and increase the likelihood of developing diseases associated with the aged, including cancer, Parkinson's, Alzheimer's and even arthritis needs to be seriously considered. Consideration of this possibility is pressing if, as proposed for thromboembolism, atherosclerosis is also initiated by unreversed ATP hydrolysis in the endothelial lining of arteries possibly developing decades in advance of overt manifestations of the chronic diseases (20). 1. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth. 1995 May;74(5):591-606. Review. 2. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement. Chest. 1999 Dec;116(6):1839-41 3. Chinner PF, Samuels DC, Elson J, Turnbull DM. Hypothesis: Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet Volume 360, Number 9342 26 October 2002 4. Fiddian-Green RG. Mitochondrial considerations bmj.com/cgi/eletters/325/7367/735/a#26019, 4 Oct 2002 5. Fiddian-Green RG Concerns about prescribing antidepressants bmj.com/cgi/eletters/325/7366/701#25874, 28 Sep 2002 6. Fiddian-Green RG Might statins cause Parkinsons? bmj.com, 18 Oct 2002 7. Misner BD. Coenzyme Q-10 Repletion bmj.com, 18 Oct 2002 8. Fiddian-Green RG . Coenzyme Q vs levodopa for Parkinson's. bmj.com, 21 Oct 2002 9. Madsen B. Re: Might statins cause Parkinsons? bmj.com, 23 Oct 2002 10. Fiddian-Green RG. Beta blockers and the risk of neurodegenerative disorders. bmj.com, 22 Oct 2002 11. Fiddian-Green RG. The real danger is in the mixing? bmj.com/cgi/eletters/325/7367/736/c#26113, 7 Oct 2002 12. Fiddian-Green RG. Intracranial compartment syndrome bmj.com/cgi/eletters/325/7364/598/a#25555, 16 Sep 2002 13. Fiddian-Green RG Functional abdominal pain: a mesenteric vascular disorder? bmj.com/cgi/eletters/325/7366/701#25838, 27 Sep 2002 14. Fiddian-Green RG Delirium: a cerebral energy deficit? bmj.com/cgi/eletters/325/7365/644#25750, 23 Sep 2002 15. Fiddian-Green RG Organic causes of the "irritable bowel syndrome". bmj.com/cgi/eletters/325/7364/555#25610, 18 Sep 2002 16. Fiddian-Green RG Functional abdominal pain: a mesenteric vascular disorder? bmj.com/cgi/eletters/325/7366/701#25838, 27 Sep 2002 17. Fiddian-Green RG Delirium: a cerebral energy deficit? bmj.com/cgi/eletters/325/7365/644#25750, 23 Sep 2002 18. Imaeda A, Tanigawa T, Aoki T, Kondo Y, Nakamura N, Yoshikawa T. Antioxidative effects of fluvastatin and its metabolites against oxidative DNA damage in mammalian cultured cells. Free Radic Res. 2001 Dec;35(6):789-801. 19. Armeni T, Battino M, Stronati A, Pugnaloni A, Tomassini G, Rosi G, Biagini G, Principato G. Total antioxidant capacity and nuclear DNA damage in keratinocytes after exposure to H2O2. Biol Chem. 2001 Dec;382(12):1697-705 20. Fiddian-Green RG. Unreversed ATP hydrolysis: the initiating endothelial event? bmj.com, 22 Oct 2002