Cytochrome c Biomarker Applications

Because cytochrome c leaves the apoptotic cell following induction of apoptosis it is being increasingly recognized as a potentially useful circulating extracellular diagnostic and prognostic biomarker for disease conditions in which apoptosis is involved.

A study of fulminant hepatitis (FH) patients found significant positive correlations in these patients between serum cytochrome c levels, levels of established serum markers for hepatitis, and the number of hepatocytes that were identified histologically as TUNEL-positive in biopsied liver samples [1]. Other studies have confirmed that serum cytochrome c levels increase with a variety of different liver disorders and that the levels correlate with the number of apoptotic cells found in the liver. Serum cytochrome c thus holds significant promise as an accessible and sensitive marker for acute liver failure.

Brain Injury
An interesting connection between the Sakaida FH study and work involving brain injury patients is the observation that circulating cytochrome c increased in FH patients immediately prior to death, while it did not increase in patients who recovered, which may indicate edemic release from injured brains in the dead patients. If true, this finding would support the established finding that injured brains release cytochrome c, and thus serum cytochrome c might not only be a potential marker for liver damage but may also be a marker for the diagnosis of brain injury and for its prognosis.

Supporting this line of inquiry is a study of pediatric traumatic brain injury (TBI) patients in which cytochrome c levels in cerbrospinal fluid were correlated with the inflicted level of TBI [2]. Since other studies have indicated that proteasomes are not involved in the early stages of necrosis progression, and thus do not affect cytochrome c release in this kind of cell death, observed increases in proteasomal proteins in TBI patients along with observed increases in cytochrome c levels may allow for the differentiation of necrotic and apoptotic neuronal cell death in TBI patients or in other brain injury patients, a distinction that has distinct therapeutic ramifications.

Systemic inflammatory response syndrome (SIRS), which can develop and progress to multiple organ dysfunction syndrome (MODS) in patients with sepsis and other inflammatory conditions, is thought to be induced by apoptosis, and indeed severely septic patients have been found to have elevated nucleosome levels. Following this line of research it has been found that serum cytochrome c levels are significantly higher in SIRS/MODS patients compared to control subjects, but that these increases do not correlate with increases in bilirubin nor creatinine [3]. This indicates that the increased cytochrome c is not the result of decreases in renal nor hepatic clearance in these patients, but is instead likely due only to release from apoptotic cells. Cytochrome c thus holds promise as a diagnostic marker for SIRS and as a prognostic marker for increased risk of MODS.

Cardiac Arrest
Cytochrome c may also be a predictor of survival from resuscitation after cardiac arrest. In a study in which ventricular defibrulation was electrically induced in rats, after which the rats were resuscitated using chest compression, circulating cytochrome c levels were negatively correlated with survival outcome [4]. The assumption is that serum cytochrome c originated from injured organs that suffered ischemia and reperfusion injury during the cardiac arrest and subsequent resuscitation. It is unclear the extent to which cytochrome c levels, while potentially progostic of survival following resuscitation, whould affect therapeutic interventions, but these findings seem to support again cytochrome c's utility as a general marker for organ failure.

Finally, because most anti-cancer drugs work by inducing apoptosis, serum cytochrome c holds promise as a prognostic marker for chemotherapy patients, and indeed several groups have reported that cytochrome c levels positively correlate with cancer therapy-induced apoptotic cell death. Furthermore, preliminary results indicate that serum cytochrome c levels correlate positively with long-term survival for cancer patients.

1. Sakaida, I. et al., J Gastroenterol 2005; 40:179-185.
2. Satchell, M. et al., Journal of Cerebral Blood Flow & Metabolism 2005; 25:919-927.
3. Adachi, N. et al., Clinica Chimica Acta 2004; 342:127-136.
4. Radhakrishnan, J. et al., Am J Physiol Heart Circ Physiol 2007; 292: H767-H775.

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