Yanev S, Kent U M, Pandova B, Hollenberg P F
Department of Drug Toxicology, Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Drug Metab Dispos. 1999 May;27(5):600-4.
Fifteen xanthates with carbon chains of different lengths or substitutions, including the antiviral compound D609 (O-tricyclo[5.2. 1.0(2,6)]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 degrees 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 microM. 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 microM, 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 a KI of 1 microM. Although the KI 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.
测试了15种具有不同长度碳链或取代基的黄原酸盐，包括抗病毒化合物D609（O - 三环[5.2.1.0(2,6)]癸 - 9 - 基 - 二硫代碳酸酯），考察它们使细胞色素P - 450（P - 450s）2B1和2B6失活的能力。所有测试的黄原酸盐均以时间和浓度依赖性方式使P - 450 2B1失活。30℃下的失活速率范围为0.22 min⁻¹至0.02 min⁻¹。半数最大失活所需浓度在2.4至69 μM之间。随着黄原酸盐碳链长度增加，可观察到失活动力学的一般趋势。较长的碳链导致失活速率较慢，失活半衰期较长且分配比更高。对于P - 450 2B1，最有效的失活剂是具有中等长度取代基的黄原酸盐。P - 450 2B1的最佳失活剂是C8黄原酸盐，失活效力（KI）为2.4 μM，失活速率为0.07 min⁻¹，分配比为4。进一步研究了4种黄原酸盐对P - 450 2B6的7 - 乙氧基 - 4 - （三氟甲基）香豆素活性的影响。C8黄原酸盐再次成为最有效的失活剂，KI为1 μM。尽管KI值通常低于P - 450 2B1的KI值，但各种黄原酸盐使P - 450 2B6失活的速率慢3至5倍。此外，用P - 450s 2E1、1A1、3A2、3A4、2C9和2D6测试了黄原酸盐的同工酶选择性。使P - 450 2E1失活的黄原酸盐浓度比使P - 450 2B1或2B6失活所需浓度高15至100倍。P - 450 1A1未被黄原酸盐失活。然而，所有测试的黄原酸盐均能在不同程度上抑制P - 450 1A1的酶活性，这取决于黄原酸盐碳链的长度。实际上未观察到P - 450s 2D6或2C9失活，除了C8和D609在高浓度（0.2 - 0.6 mM）时具有抑制作用。所研究的黄原酸盐均对P - 450s 3A2或3A4的活性没有任何影响。
