Turteltaub K W, Vogel J S, Frantz C, Felton J S, McManus M
Biomedical and Biotechnology Research Program/Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
Princess Takamatsu Symp. 1995;23:93-102.
Estimating the cancer risk posed by heterocyclic amines depends on measuring how chemical dose influences measurable indicators of cancer progression. This data ideally should encompass the range of actual human exposure, at the low dose end, and laboratory animal studies, at the high dose end. Accelerator mass spectrometry (AMS) has been used to measure the absorption, fate, and DNA adduct dosimetry of the heterocyclic amines PhIP and MeIQx at doses equivalent to human consumption following single-dose administration and chronic daily dosing. AMS is a nuclear physics technique which specifically counts nuclei of cosmogenic isotopes, rather than relying on decay. For tracing 14C, sensitivity is increased 10(6)-fold relative to decay counting. We have found that tissue clearance rates for [2-(14)C]-PhIP are rapid (t1/2 = 1 h) at low dose (41 ng/kg), with most of the radiocarbon distributed to the liver and G.I. tract. MeIQx-DNA adduct levels decrease linearly with dose (5 mg/kg-500 ng/kg) in single dose exposures. Likewise, the biologically available dose of [2-(14)C]-MeIQx decreases linearly with decreasing dose (5 mg/kg-1 ng/kg). On chronic daily dosing, it takes 40 days for adducts to reach steady-state in tissues and adduct levels appear to decrease linearly with decreasing dose, except possibly at very low doses. DNA binding of PhIP involves both sulfation or acetylation of the N-hydroxylated PhIP. Quantitatively, sulfation appears to be an important pathway for PhIp activation in rodent tissue cytosols while acetylation appears quantitatively more important in human tissue cytosols. The greatest activity is in liver and intestinal tissues for both pathways. The specific DNA adducts formed in vivo and in vitro from exposure to PhIP and MeIQx are likely guanine adducts. These data suggest that DNA adduct dosimetry responds linearly with dose but may become sub-linear at very low doses for chronic exposure and that factors other than DNA adduction may be critical to explain these heterocyclic amines' tumorigenicity.
评估杂环胺所带来的癌症风险，取决于测定化学剂量如何影响癌症进展的可测量指标。理想情况下，这些数据应涵盖实际人类接触的剂量范围（低剂量端）以及实验室动物研究的剂量范围（高剂量端）。加速器质谱法（AMS）已被用于测量杂环胺PhIP和MeIQx在单剂量给药和慢性每日给药后相当于人类摄入量的剂量下的吸收、归宿和DNA加合物剂量测定。AMS是一种核物理技术，它专门对宇宙成因同位素的原子核进行计数，而不是依赖于衰变。对于追踪14C，相对于衰变计数，灵敏度提高了10^6倍。我们发现，在低剂量（41 ng/kg）下，[2-(14)C]-PhIP的组织清除率很快（t1/2 = 1小时），大部分放射性碳分布到肝脏和胃肠道。在单剂量暴露中，MeIQx-DNA加合物水平随剂量（5 mg/kg - 500 ng/kg）呈线性下降。同样，[2-(14)C]-MeIQx的生物可利用剂量随剂量降低（5 mg/kg - 1 ng/kg）呈线性下降。在慢性每日给药时，加合物需要40天才能在组织中达到稳态，并且加合物水平似乎随剂量降低呈线性下降，可能极低剂量除外。PhIP与DNA的结合涉及N-羟基化PhIP的硫酸化或乙酰化。从数量上看，硫酸化似乎是啮齿动物组织胞质溶胶中PhIp活化的重要途径，而乙酰化在人类组织胞质溶胶中在数量上似乎更重要。两种途径在肝脏和肠道组织中的活性最高。体内和体外暴露于PhIP和MeIQx形成的特定DNA加合物可能是鸟嘌呤加合物。这些数据表明，DNA加合物剂量测定随剂量呈线性反应，但在慢性暴露的极低剂量下可能变为亚线性，并且除了DNA加合之外的因素可能对解释这些杂环胺的致瘤性至关重要。
