RT Journal Article
SR Electronic
T1 Selective Mechanism-Based Inactivation of Cytochromes P-450 2B1 and P-450 2B6 by a Series of Xanthates
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 600
OP 604
VO 27
IS 5
A1 Yanev, Stanislav
A1 Kent, Ute M.
A1 Pandova, Bozidarka
A1 Hollenberg, Paul F.
YR 1999
UL http://dmd.aspetjournals.org/content/27/5/600.abstract
AB Fifteen xanthates with carbon chains of different lengths or substitutions, including the antiviral compound D609 (O-tricyclo[5.2.1.02,6]dec-9-yl-dithiocarbonate), were tested for their ability to inactivate cytochromes P-450 (P-450s) 2B1 and 2B6. All of the xanthates tested were found to inactivate P-450 2B1 in a time- and concentration-dependent manner. The rates of inactivation at 30°C ranged from 0.22 min−1 to 0.02 min−1. The concentrations required for half-maximal inactivation were between 2.4 and 69 μM. A general trend in the inactivation kinetics could be observed with an increasing chain length of the xanthates. Longer carbon chains resulted in slower rates of inactivation with longer half-times of inactivation and higher partition ratios. For P-450 2B1, the most effective inactivators were xanthates with substitutions of intermediate length. The best inactivator for P-450 2B1 was the C8 xanthate, with an inactivation potency (KI) of 2.4 μM, a rate of inactivation of 0.07 min−1, and a partition ratio of 4. Four xanthates were further examined for their effect on the 7-ethoxy-4-(trifluoromethyl)coumarin activity of P-450 2B6. The C8 xanthate was again the most effective inactivator, with aKI of 1 μM. Although theKI values were generally lower than those found with P-450 2B1, the rates of inactivation for P-450 2B6 with the various xanthates were 3- to 5-fold slower. In addition, the isozyme selectivity of xanthates was tested with P-450s 2E1, 1A1, 3A2, 3A4, 2C9, and 2D6. P-450 2E1 was inactivated by xanthates at concentrations 15- to 100-fold higher than those required to inactivate either P-450 2B1 or 2B6. P-450 1A1 was not inactivated by xanthates. However, all of the xanthates tested were able to inhibit the enzymatic activity of P-450 1A1 to a different extent, depending on the length of the xanthate carbon chain. Virtually no inactivation of P-450s 2D6 or 2C9 was seen, except that C8 and D609 were inhibitory at high concentrations (0.2–0.6 mM). None of the xanthates studied had any effect on the activities of P-450s 3A2 or 3A4. The American Society for Pharmacology and Experimental Therapeutics