Phase 2: The Next Step in Controlling Inflammation in Arthritis and Atherosclerosis

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 4 • October 2005

Phase 2: The Next Step in Controlling Inflammation in Arthritis and Atherosclerosis

New information on regulatory pathways controlling inflammation in arthritis and atherosclerosis appears in a new paper.1

One source of inflammation to chondrocytes (cells in joints that produce cartilage) and endothelial cells (which line blood vessels) is fluid shear, the stress of fluids moving against adjacent cells. As the paper explains, high shear is protective to endothelial cells by inducing antioxidant and phase 2 detoxifying genes. In joints, however, high shear causes irreversible matrix erosion and chondrocyte apoptosis. In fact, high shear in joints causes an upregulation of COX-2 expression, hence the use of COX-2 inhibitors to treat arthritis inflammatory pain. “Phase 2 inducers and to a lesser extent specific inhibitors of COX-2 negate the shear-mediated repression of ARE [antioxidant response element] regulated enzyme activity and apoptosis.”

As the authors further explain, “. . . recent evidence that the shear-induced upregulation of phase 2 genes in human aortic endothelial cells is attenuated by COX-2 specific inhibitors may contribute to their cardiovascular side effects. Whereas COX-2 inhibitors reduce inflammation in cartilage, their presence in the vasculature prevents the accumulation of COX-2-derived 15d-PGJ2, which is associated with the atheroprotective nature of laminar flow. Consequently, phase 2 inducers represent an attractive and safe alternative to COX-2 inhibitors based on their anti-inflammatory potential and their highly beneficial antioxidative properties. [Emphasis added]

“Phase 2 proteins, mainly enzymes, include the classical ones, such as NAD(P)H:quinone oxidoreductase 1, glutathione-S-transferases, UDP-glucuronosyl transferases, as well as the more recently defined proteins ferritin H, metallothioneins, cystine/glutamate antiporter, and L-gamma-glutamyl-L-cysteine ligase. Phase 2 protein genes are coordinately upregulated through activation of an antioxidant response element (ARE) . . .”7

Dietary ingredients that induce phase 2 enzymes include curcumin,2,3 extracts of broccoli, green onion, green cabbage, purple cabbage, black cabbage, and cauliflower,4 as well as asparagus, celery, and eggplant,5 and green tea.6 As one study7 explained, “A potent phase 2 protein inducer is sulforaphane, the isothiocyanate metabolite of the glucosinolate glucoraphanin. Glucosinolates are beta-thioglucoside N-hydroxysulfates present in 16 families of higher plants with the distribution in the family Brassicaceae, particularly the genus Brassica . . .” Brassica vegetables include broccoli, cauliflower, and related cruciferous types. Seabuckthorn8 was also reported to be a phase 2 inducer. Quercetin was reported9 to induce glutathione concentration and the activity of the phase 2 enzyme gamma-glutamylcysteine synthetase, the rate-limiting enzyme of glutathione synthesis. Although not a natural dietary ingredient, BHT is also an inducer of phase 2 enzymes. Copper and zinc induce metallothioneins.


  1. Healy et al. Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis. Proc Natl Acad Sci USA 102(39):14010-5 (2005).
  2. Sharma et al. Antioxidant role of glutathione-S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis. Antiox Redox Signal 6(2):289-300 (2004).
  3. Iqbal, Sharma, et al. Dietary supplementation of curcumin enhances antioxidant and phase 2 metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol 92:33-8 (2003).
  4. Laso et al. Induction of NAD(P)H quinone oxidoreductase by vegetables widely consumed in Catalonia, Spain. Nutr Cancer 52(1):49-58 (2005).
  5. Yeh, Yen. Effect of vegetables on human phenolsulfotransferases in relation to their antioxidant activity and total phenolics. Free Rad Res 39(8):893-904 (2005).
  6. Lin et al. Hypolipidemic effect of green tea leaves through induction of antioxidant and phase 2 enzymes including superoxide dismutase, catalase, and glutathione-S-transferase in rats. J Agric Food Chem 46(5):1893-9 (1998).
  7. Noyan-Ashraf et al. Dietary approach to decrease aging-related CNS inflammation. Nutr Neurosci 8(2):101-10 (2005).
  8. Padmavathi et al. Chemoprevention by Hippophae rhamnoides: effect on tumorigenesis, phase 2 and antioxidant enzymes, and IRF-1 transcription factor. Nutr Cancer 51(1):59-67 (2005).
  9. Schart et al. Enhancement of glutathione and gamma-glutamylcysteine synthetase, the rate-limiting enzyme of glutathione synthesis, by chemoprotective plant-derived food and beverage components in the human hepatoma cell line HepG2. Nutr Cancer 45(1):74-83 (2003).

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