Effects of Pycnogenol on Microsomal Cytochrome P450 Activity and Apoptosis

Phytochemicals are naturally-occurring compounds found in plants, many of which are consumed as nutritional supplements by humans. Pycnogenol is a mixture of flavonoid compounds extracted from bark of pine trees (Pinus maritima) and is commercially available in several different pharmaceutical preparations as a free radical scavenger. Since few scientific studies have documented the pharmacologic effects of pycnogenol, our objective was to characterize the biological activity of pycnogenol. One study looked at the effects of pycnogenol on the three pathways of NNK metabolism: NNK reduction, N-oxidation and a-hydroxylation. NNK is a lung carcinogen. Lung and liver microsomes from 6 mo and 20 mo old male F344 rats were incubated with 3H-NNK in the presence of pycnogenol and following intragastric administration of pycnogenol. Pycnogenol inhibited the in vitro metabolism of NNK in both liver and lung microsomes from both age groups. Intragastric administration of pycnogenol enhanced a-hydroxylation of NNK in liver microsomes and N-oxidation of NNK in lung microsomes from either age group. Metabolic activation of NNK depends upon cytochrome P450 enzymes (GYP). A second study looked at O-dealkylation of the substrates benzyloxyresorufin (BROD), ethoxyresorufin (EROD) and methoxyresorufin (MROD) linked to CYP2B1,2C6 and 1A2, respectively. Pycnogenol significantly inhibited BROD, EROD and MROD activity in 6 mo and 20 mo liver microsomes and inhibited BROD activity but enhanced EROD and MROD in both 6 mo and 20 mo lung microsomes. Following intragastric administration, pycnogenol inhibited BROD, EROD and MROD in both 6 mo and 20 mo liver microsomes. Pycnogenol inhibited MROD activity but enhanced EROD in 6 mo and 20 mo lung microsomes. Results from Western blot analysis of expressed CYP2B1 and CYP1A2 protein in lung and liver microsomes from pycnogenol-treated rats did not correlate with the effects of O-dealkylation in these rats. The effect of pycnogenol on apoptosis in cultured normal human mammary (MCF-10) cells and human mammary cancer (MCF-7) cells in the presence of pycnogenol was also investigated. At 80 |ng/ml pycnogenol, apoptosis in MCF-7 cells was significantly increased but had no effect on apoptosis in MCF-10 cells. We conclude that pycnogenol may afford protection against NNK-induced lung cancer by modulating NNK metabolism and the activity of cytochrome P450 enzymes. Pycnogenol may also selectively induce apoptosis in cancer cells