Mechanistic studies on hepatotoxicity of chloroacetanilide herbicides and hematotoxicity of munitions compound RDX and environmental degradation product MNX
Kale, VM
| HERO ID | 1065803 |
|---|---|
| Year | 2007 |
| Title | Mechanistic studies on hepatotoxicity of chloroacetanilide herbicides and hematotoxicity of munitions compound RDX and environmental degradation product MNX |
| Authors | Kale, VM |
| City | Monroe, LA |
| Abstract | We hypothesized that CYP3A N -dealkylation of alachlor is a key determinant in hepatocyte cytotoxicity and that such metabolism has relevance to human hepatotoxicity. Results show that highly N -dealkylated chloroacetanilides alachlor and acetochlor were potent cytotoxicants compared to negligible N -dealkylated metolachlor to Sprague-Dawley (SD) rat hepatocytes (NRH). Higher cytotoxicity of N -dealkylated alachlor metabolite CDEPA in NRH suggests that N -dealkylation is a bioactivation process. Sensitization to alachlor cytotoxicity in hepatocytes from dexamethasone-pretreated rats (DRH), and lower alachlor cytotoxicity with a potent CYP3A inhibitor (clotrimazole) correlated with the rate of CDEPA formation supports a critical role of CYP3A N -dealkylation. In contrast, alachlor cytotoxicity in cryopreserved human hepatocytes is inversely correlated with CYP3A4 indicating its involvement in detoxication. Further, comparable cytotoxicity of alachlor, acetochlor, and metolachlor suggests species-specific mechanisms of toxicity for these chloroacetanilides with a greater relative risk of adverse effects from metolachlor in humans than predicted from rat studies. RDX (hexahydro-1,3,5-trinitro-1,3,5-trazine) is widely used munitions compound and now contaminate soil and ground water at artillery training and manufacturing sites. RDX is anaerobically degraded to mono di and tri N -nitroso products MNX, DNX and TNX, respectively. MNX is the most potent of three degradation products in-terms of LD 50 and anemia. We hypothesized that transformation of RDX to MNX decreases hematotoxicity. Results are obtained from studies conducted using female SD rats indicate that 14-day acute oral exposure to RDX and MNX resulted in anemia (NOAEL 47 mg/kg). RDX was more potent than MNX in decreasing peripheral blood leukocytes and bone marrow cellularity. RDX and MNX were found to decrease Burst Forming Units-Erythroblasts (BFU-E, NOAEL 12 mg/kg) and Granulocyte Macrophage-Colony Forming Units (CFU-GM, NOAEL < 12 mg/kg) 14 days after exposure. Stimulation of the Colony Forming Units-Granulocyte, Erythrocyte, Monocyte, Macrophage (CFU-GEMM) at lower doses and no effects with CFU-GM and BFU-E were observed after 7-day acute exposure. Flow cytometry analysis revealed no change in cell surface expression CD71 and Thy1.1 markers. In conclusion, reduction of RDX to MNX is a detoxification process and may affect growth of a relatively proximal committed stem cell population in hematopoiesis. |
| Url | http://proquest.umi.com/pqdlink?did=1445039451&Fmt=7&clientI d=79356&RQT=309&VName=PQD |
| Is Certified Translation | No |
| Dupe Override | No |
| University Name | University of Louisiana at Monroe |
| Paper Level | Doctoral Dissertation |
| Comments | ISBN 9780549372608 |
| Is Public | Yes |
| Is Qa | No |