Role of hypoxia and constitutionally different resistance to hypoxia/stress as the determiners of individual profile of cytochrome P450 isozyme activity.

摘要

The hepatic cytochromes P450 1A1, 1A2, 2B1, and 2E1 activities have been investigated in the sublines of Wistar rats with principally different (high or low) resistance to hypoxia/stress. Repeated measurements in normoxic conditions showed a significant prevalence of total cytochrome P450 content, CYP 1A1, and CYP 2E1 activities in rats with low-resistance (LR) to hypoxia compared to rats with high-resistance to hypoxia (HR), whereas in HR rats the CYP 1A2 activity was 63% higher (p < 0.001) than in LR rats. In the conditions of acute hypobaric hypoxia these differences were manifested distinctly: in HR rats an enhancement of CYP 1A2 activity by 49% of aerobic value (p < 0.01) was observed, in LR rats the total P450 content, CYP 1A1 and 2E1 activities (p < 0.05-0.001) were increased. The 30-min total liver ischemia formed an individual response of the drug-metabolizing system: in HR rats CYP 1A2 and 2B1 activities were decreased in the early postischemic period and were not restored by the 21st day, whereas in LR rats CYP 1A2 activity was not affected and was induced more than 2-fold of aerobic value in the late post-ischemic period. The CYP 2B1 activity was induced almost 1.5-fold during the whole postischemic period. These data suggest that acute hypoxia and individual resistance to hypoxia/stress, one of the cardinal constitutional features, provide an individual reaction of drug-metabolizing system and enzymes of P450, in particular. The individual constitutional resistance to hypoxia/stress may be a serious criterion for an individual approach in pharmacotherapy of hypoxic states, diseases, as well as for prognosis and prevention of early and distant complications of irrational pharmacotherapy.