Nomeir A A, Matthews H B
Toxicology Research and Testing Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
J Toxicol Environ Health. 1997 Aug 8;51(5):489-501. doi: 10.1080/00984109708984039.
A study of dimethyl hydrogen phosphite (DMHP) by the National Toxicology Program (NTP) indicated that chronic administration by oral gavage resulted in an increased incidence of neoplastic lesions in the lungs and forestomachs of Fischer 344 rats but not in B6C3F1 mice. The current study was designed to evaluate the metabolic basis, if any, of this species selectivity by studying the metabolism and disposition of [14C]DMHP in the respective strains of rats and mice. Results of this study indicate that DMHP administered at a range of dose of 10-200 mg/kg was readily and near completely absorbed from the gastrointestinal tracts of rats and mice. DMHP-derived radioactivity was eliminated primarily as CO2 in the expired air, 44-57%, and urine, 28-49%, and very little was collected in feces, 1-2%, or as volatile organics, 2-3%. DMHP-derived radioactivity was widely distributed in tissues of rats and mice, with the highest concentrations observed in the liver, kidneys, spleen, lungs, and forestomach, and the lowest in brain, skeletal muscle, and adipose tissue. The disappearance of radioactivity from mouse tissues was approximately twice as rapid as from rat tissues. In vitro, DMHP was metabolized to formaldehyde by the microsomal fractions of liver, lungs, kidneys, forestomach, and glandular stomach. In vivo, DMHP was metabolized to the product of demethylation, monomethyl hydrogen phosphite (MMHP), which was excreted in urine. Results of this study indicate that the NTP carcinogenicity study with DMHP was carried out within the dose range in which the absorption, metabolism, and disposition of DMHP are linear in both species. Apparent species-dependent differences in the metabolism and disposition of DMHP are limited to the more rapid metabolism and elimination by the mouse. Therefore, the species-dependent variations in the carcinogenicity of DMHP are most likely attributable to factors other than metabolism and disposition.
美国国家毒理学计划（NTP）对亚磷酸二甲酯（DMHP）的一项研究表明，通过口服灌胃长期给药会导致Fischer 344大鼠肺部和前胃的肿瘤性病变发生率增加，但对B6C3F1小鼠则无此影响。本研究旨在通过研究[14C]DMHP在大鼠和小鼠各品系中的代谢和处置情况，评估这种物种选择性的代谢基础（如有）。本研究结果表明，以10 - 200 mg/kg的剂量范围给药时，DMHP在大鼠和小鼠的胃肠道中易于吸收且几乎完全吸收。DMHP衍生的放射性主要以呼出气体中的二氧化碳形式（44 - 57%）和尿液形式（28 - 49%）消除，粪便中收集到的极少（1 - 2%），挥发性有机物中收集到的也很少（2 - 3%）。DMHP衍生的放射性广泛分布于大鼠和小鼠的组织中，在肝脏、肾脏、脾脏、肺和前胃中浓度最高，在脑、骨骼肌和脂肪组织中浓度最低。小鼠组织中放射性的消失速度约为大鼠组织的两倍。在体外，DMHP被肝脏、肺、肾脏、前胃和腺胃的微粒体部分代谢为甲醛。在体内，DMHP被代谢为去甲基化产物亚磷酸单甲酯（MMHP），并通过尿液排出。本研究结果表明，NTP对DMHP的致癌性研究是在DMHP在两种物种中的吸收、代谢和处置均呈线性的剂量范围内进行的。DMHP在代谢和处置方面明显的物种依赖性差异仅限于小鼠代谢和消除速度更快。因此，DMHP致癌性的物种依赖性差异最有可能归因于代谢和处置以外的因素。
