Журнал лекарственного метаболизма и токсикологии
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Lead and its Effects on Cytochromes P450

Lowry JA1, Pearce RE, Gaedigk, Venneman, Talib N, Shaw P, Leeder JS and Kearns GL

Background: The adverse effects of lead on heme biosynthesis and production of anemia are well known. Lead may disrupt the normal activity of other hemoproteins, such as cytochromes P450 (CYP) which are responsible for drug metabolism. While data in animals suggest a decrease in CYP function with lead exposure, there is little data in humans.
Methods: After IRB approval, consented patients with asymptomatic, low to moderate level (10 mg/dl to 44 mg/ dl) lead poisoning were assessed for CYP1A2 and CYP2D6 activity at diagnosis, 1 month, 2 months and after lead level was less than 10 mg/dl. Low doses of caffeine (CYP1A2 activity) and dextromethorphan (DM) (CYP2D6 activity) were administered and urine collected for 12-24 hours at each visit. Lead levels, free erythrocyte protoporphyrin, and iron studies were performed as well. A mixed linear model was used to analyze the data. CYP2D6 genotyping was performed using PCR techniques.
Results: Eleven out of the sixteen eligible children (7 males, 4 Caucasian, average age: 33 months) completed the study. Average time to complete the study was 20 months. Seven had lead levels between 10-25 mcg/dl. Eight had elevated EPP. None had low iron levels. A random intercepts mixed linear model was fit to the data. No statistical significance was found for CYP1A2 or CYP2D6 metabolic ratio related to the lead level, change in lead level or time. Discussion: Lead was found to have no effect on the CYP drug metabolizing enzymes at low blood lead levels. Lead has been shown to effect multiple sites on the hemoglobin synthesis pathway resulting in elevated EPP at lead levels >10 mg/dl. However, threshold for decreased hemoglobin levels in children is judged to be approximately 40 μg/dL. Thus, cytochromes may not be affected until higher lead levels are seen. The size of the study limits generalizability.
Conclusion: Based on this study, no changes in drug treatment for children with low blood lead levels are necessary. However, further studies may be needed to assess the effect from higher blood lead levels.