Biochemical and Biophysical Research Communications
In vitro assessment of inhibition by natural polyphenols of metabolic activation of procarcinogens by human CYP1A1☆,☆☆
Section snippets
Materials
Apigenin, myricetin, kaempferol, quercetin, naringenin, hesperetin, naringin, hesperidin, rutin, resveratrol, (−)-epigallo catechin gallate, 7-ethoxyresorufin, resorufin, B[a]P, and DLPC were purchased from Sigma. 7,8-diol-B[a]P and the tetraols RTTC, RTTT, RTCT, and RTCC were purchased from NCI Chemical Carcinogen Repository, Midwest Research Institute, Kansas City, MI, USA. 3-OH-B[a]P was a gift of Dr. A. Seidel (University Mainz, Germany).
Expression, purification, and reconstitution of human CYP1A1 and human P450 reductase
Construction of the modified CYP1A1 cDNA, cloning
Inhibition of different CYP1A1 activities by resveratrol and (−)-epigallo catechin gallate
In preliminary experiments, we determined the apparent Km values for the formation of DE2 from 7,8-diol-B[a]P, the formation of 3-OH-B[a]P from B[a]P, and the EROD reaction. These values were 1, 5.2, and 0.4 μM, respectively. In the present study, inhibitor concentrations were in the order of magnitude of the Km values or about two times higher. Thus, the concentrations of substrates were 2 μM (7,8-diol-B[a]P), 5 μM (B[a]P), and 0.5 μM (ethoxyresorufin).
The effects of resveratrol and (−)-epigallo
Acknowledgements
We are grateful to Dr. F.J. Gonzalez for providing CYP1A1 cDNA and virus for P450 reductase expression (National Cancer Institute, NIH, Bethesda, MD, USA) and to Dr. A. Seidel (Institute for Toxicology, University Mainz, Germany) for a sample of 3-OH-B[a]P. We thank Dr. A. Chernogolov, Dr. H. Honeck, C. Andreé, and A. Sternke (all from Max Delbrueck Center for Molecular Medicine, Berlin-Buch) for preparational work, assistance in HPLC and cell culturing. This work was supported by grants of the
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Part of work was presented at the MDO2002, Sapporo, Japan, July 22–26, 2002.
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Abbreviations: CYP1A1, human cytochrome P450 1A1; P450 reductase, NADPH cytochrome P450 reductase; B[a]P, benzo[a]pyrene; 7,8-diol-B[a]P, B[a]P-trans-7,8-dihydrodiol; RTTC, r-7,t-8,t-9,c-10-tetrahydroxy-7,8,9,10-tetrahydro-B[a]P; RTTT, r-7,t-8,t-9,t-10-tetrahydroxy-7,8,9,10-tetrahydro-B[a]P; RTCT, r-7,t-8,c-9,t-10-tetrahydroxy-7,8,9,10-tetrahydro-B[a]P; RTCC, r-7,t-8,c-9,c-10-tetrahydroxy-7,8,9,10-tetrahydro-B[a]P; diolepoxide 2, DE2, (±)-B[a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide; diolepoxide 1, DE1, (±)-B[a]P-r-7,t-8-dihydrodiol-c-9,10-epoxide; DLPC, dilaurylphosphatidylcholine; EROD, 7-ethoxyresorufin O-deethylation; AHH, aryl hydrocarbon hydroxylation.