Glatt H, Werle-Schneider G, Enders N, Monnerjahn S, Pudil J, Czich A, Seidel A, Schwarz M
Department of Toxicology, German Institute of Human Nutrition, Potsdam-Rehbrücke.
Chem Biol Interact. 1994 Jun;92(1-3):305-19. doi: 10.1016/0009-2797(94)90072-8.
1-Hydroxymethylpyrene (HMP) is activated to a potent mutagen, detectable in Salmonella typhimurium, in the presence of hepatic cytosol, cofactor for sulfotransferases, and chloride anions. The number of induced mutations is linear to the amount of cytosol used over a wide range, allowing for the quantification of this activity. The activity is expressed with high selectivity in certain tissues and cell types. In adult rats, the highest level is found in the liver, the activity in females exceeding that in males about threefold. About half of the activity in the liver of females is provided by hydroxysteroid sulfotransferase a (STa), whereas other enzymes may be more important in males on account of their very low level of STa. The expression of STa is decreased in ATPase-negative, presumably preneoplastic, hepatic foci in female rats. In contrast to its high mutagenicity in bacteria, SMP shows only weak mutagenic activity in mammalian cells (Chinese hamster V79 cells), independently of whether it is externally added, or generated from HMP within the cells by heterologously expressed STa. Sulfation, however, strongly enhances the cytotoxicity of HMP in mammalian cells. The high cytotoxicity and low mutagenicity in mammalian cells in culture have possible correlates in vivo: while HMP is only a weak initiator of ATPase-negative hepatic foci in newborn rats, it shows substantial promoting activity with regard to such foci in female, but not in male rats. We postulate that this promotion results from selective toxification by STa in the normal hepatic parenchyma of female rats, and resistance of ATPase/STa-negative foci.
1-羟甲基芘（HMP）在肝胞质溶胶、磺基转移酶的辅因子和氯离子存在的情况下，会被激活成为一种可在鼠伤寒沙门氏菌中检测到的强效诱变剂。在很宽的范围内，诱导突变的数量与所用胞质溶胶的量呈线性关系，从而可以对这种活性进行定量。这种活性在某些组织和细胞类型中具有高度选择性地表达。在成年大鼠中，肝脏中的活性水平最高，雌性大鼠的活性比雄性大鼠高出约三倍。雌性大鼠肝脏中约一半的活性由羟类固醇磺基转移酶a（STa）提供，而由于雄性大鼠中STa水平极低，其他酶可能更为重要。在雌性大鼠中，ATP酶阴性、可能为癌前病变的肝灶中STa的表达会降低。与它在细菌中的高诱变性不同，SMP在哺乳动物细胞（中国仓鼠V79细胞）中仅表现出微弱的诱变活性，无论它是外部添加的，还是通过异源表达的STa在细胞内由HMP产生的。然而，硫酸化会强烈增强HMP在哺乳动物细胞中的细胞毒性。培养的哺乳动物细胞中高细胞毒性和低诱变性在体内可能存在相关情况：虽然HMP在新生大鼠中只是ATP酶阴性肝灶的弱启动剂，但它在雌性大鼠而非雄性大鼠中对这类病灶具有显著的促进活性。我们推测这种促进作用是由雌性大鼠正常肝实质中的STa选择性解毒以及ATP酶/STa阴性病灶的抗性导致的。
