Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity
Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity
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DOI：
10.2307/3433165
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发表时间：
1996-12-01
影响因子：
10.4
通讯作者：
Tichavska, B
中科院分区：
文献类型：
--
作者：
Gut, I;Nedelcheva, V;Tichavska, B
细胞色素P450（CYP 2 E1）是大鼠和人肝微粒体中最有效的苯氧化酶。共价结合主要是由于苯醌（BQ），氢醌（HQ）的氧化产物的形成，并与可溶性代谢产物的形成呈负相关。在大鼠中，吸入苯（14 mg/L空气）导致先前由苯巴比妥诱导的CYP 2B 1迅速破坏。苯代谢产物体外破坏肝微粒体脂质的能力依次为BQ > HQ >邻苯二酚>苯酚。抗坏血酸逆转的破坏和减少α-生育酚，表明HQ是无毒的，而BQ和半醌自由基（SQ）引起的效果。在还原型烟酰胺腺嘌呤二核苷酸磷酸盐（NADPH）存在下，微粒体不将HQ氧化为BQ，而HQ和BQ产生的超氧阴离子自由基则被显著淬灭。HQ或BQ在体外引起的细胞凋亡的破坏不是由羟基自由基形成或脂质过氧化介导的。相反，HQ和BQ抑制NADPH介导的脂质过氧化。抗坏血酸诱导高水平的羟基自由基的形成和脂质过氧化，这是不同的影响醌类，表明不同的机制。尽管降低了HQ和BQ的毒性，但抗坏血酸似乎诱导其自身的毒性，反映在高水平的脂质过氧化反应中。铁氧化还原循环在NADPH诱导的羟基自由基的形成中发挥了重要作用，但在抗坏血酸引起的氧化还原循环中没有发挥重要作用;然而，由NADPH或抗坏血酸诱导的脂质过氧化反应被乙二胺四乙酸抑制，表明铁的重要作用。因此，数据表明，醌类直接而不是通过氧活化或脂质过氧化作用来破坏脂质。
Cytochrome P450 (CYP) 2E1 was the most efficient CYP enzyme that oxidized benzene to soluble and covalently bound metabolites in rat and human liver microsomes. The covalent binding was due mostly to the formation of benzoquinone (BQ), the oxidation product of hydroquinone (HQ), and was inversely related to the formation of soluble metabolites. In rats, inhalation of benzene 14 mg/liter of air) caused a rapid destruction of CYP2B1 previously induced by phenobarbital. The ability of benzene metabolites to destroy liver microsomal CYP in vitro decreased in the order BQ > HQ > catechol > phenol. The destruction was reversed by ascorbate and diminished by alpha-tocopherol, suggesting that HQ was not toxic, whereas BQ and semiquinone radical (SQ) caused the effect. in the presence of nicotinamide adenine dinucleotide phosphate, reduced (NADPH) the microsomes did not oxidize HQ to BQ, while the formation of superoxide anion radical from both HQ and BQ was markedly quenched. Destruction of CYP in vitro caused by HQ or BQ was not mediated by hydroxyl radical formation or by lipid peroxidation. On the contrary, HQ and BQ inhibited NADPH-mediated lipid peroxidation. Ascorbate induced high levels of hydroxyl radical formation and lipid peroxidation, which were differentially affected by quinones, indicating different mechanisms. Despite reducing the toxicity of HQ and BQ, ascorbate appeared to induce its own toxicity, reflected in high levels of lipid peroxidation. Iron redox cycling played a significant role in the NADPH-induced hydroxyl radical formation but not in that caused by ascorbate; however, lipid peroxidation induced by NADPH or ascorbate was suppressed by ethylenediaminetraacetate, indicating a crucial role of iron. Thus, the data indicate that the quinones destroyed CYP directly and not via oxygen activation or lipid peroxidation.