Deyo J A, Reed R L, Buhler D R, Kerkvliet N I
College of Veterinary Medicine, Oregon State University, Corvallis 97331-7301.
Toxicology. 1994 Nov-Dec;94(1-3):209-22. doi: 10.1016/0300-483x(94)90039-6.
Monocrotaline (MCT) is a pyrrolizidine alkaloid which has been shown to induce immunotoxicity in mice. We hypothesized that metabolic activation of MCT by mixed-function oxygenases (MFO) to dehydromonocrotaline (MCTP) is a prerequisite for its immunotoxicity, as has been shown for other toxic effects of MCT. To test this hypothesis, we compared the in vitro immunotoxic potency of MCT and MCTP to suppress the in vitro antibody response to SRBC and the blastogenic response to B and T cell mitogens. In addition, the effects of in vivo modulation of MFO activities on the immunotoxicity of MCT was examined using phenobarbital (PB) to increase and chloramphenicol (CP) to decrease MCTP production. Results showed that in vitro exposure of splenic lymphocytes to MCT or MCTP produced significant suppression of the antibody and blastogenic responses. MCTP was 200-400-fold more potent than MCT. No metabolism of MCT by splenic cells was detectable, suggesting that unmetabolized MCT is capable of inducing immunotoxicity. In vivo studies showed that, while treatment of mice with PB or CP produced significantly increased and decreased MCTP production by liver microsomes, neither PB or CP treatment significantly altered the immunotoxic potency of MCT. Thus, while the MCTP metabolite is directly immunotoxic in vitro and much more potent than MCT, a role for the MCTP metabolite in MCT immunotoxicity in vivo could not be demonstrated.
野百合碱（MCT）是一种吡咯里西啶生物碱，已被证明可在小鼠中诱导免疫毒性。我们假设，混合功能氧化酶（MFO）将MCT代谢活化为脱氢野百合碱（MCTP）是其免疫毒性的前提条件，就像MCT的其他毒性作用所显示的那样。为了验证这一假设，我们比较了MCT和MCTP在体外抑制对绵羊红细胞（SRBC）的抗体反应以及对B细胞和T细胞有丝分裂原的增殖反应的免疫毒性效力。此外，使用苯巴比妥（PB）来增加MCTP的产生以及氯霉素（CP）来减少MCTP的产生，研究了体内调节MFO活性对MCT免疫毒性的影响。结果表明，体外将脾淋巴细胞暴露于MCT或MCTP会显著抑制抗体反应和增殖反应。MCTP的效力比MCT高200 - 400倍。未检测到脾细胞对MCT的代谢，这表明未代谢的MCT能够诱导免疫毒性。体内研究表明，虽然用PB或CP处理小鼠会使肝微粒体产生的MCTP显著增加或减少，但PB或CP处理均未显著改变MCT的免疫毒性效力。因此，虽然MCTP代谢物在体外具有直接免疫毒性且比MCT强得多，但无法证明MCTP代谢物在MCT体内免疫毒性中起作用。
