Malekinejad H, Maas-Bakker R, Fink-Gremmels J
Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, The Netherlands.
Vet J. 2006 Jul;172(1):96-102. doi: 10.1016/j.tvjl.2005.03.004.
Zearalenone (ZEA), a Fusarium toxin, is frequently found in animal feed materials. It is known to exert oestrogenic effects in all animals tested but susceptibility varies between species, possibly reflecting differences in the metabolic processing of ZEA, which predominantly involves hydroxylations, assumed to be catalysed by 3alpha- and 3beta- hydroxysteroid dehydrogenases, as well as conjugation with glucuronic acid. In this study, the biotransformation of ZEA by hepatic subcellular fractions of various domestic animals was investigated and compared to the rat. Notable inter-species differences in terms of the rate of absolute and relative metabolite production in the different subcellular fractions were identified. The highest amount of alpha-zearalenol (alpha-ZOL) was produced by pig hepatic microsomes (V(max)=795.8+/-122.7pmol/mg/min), whereas in chicken microsomes the highest amounts of beta-zearalenol (beta-ZOL) (V(max)=1524+/-29.7pmol/mg/min) could be measured. Except for sheep and cattle, the efficiency of alpha-ZOL production (expressed as the ratio of apparent V(max)/k(m)) was higher in the microsomal fraction compared to the post-mitochondrial fraction. In contrast, the apparent efficiency of beta-ZOL production was high in pigs, cattle, chickens and rats, but very low in sheep. Conjugation of ZEA with glucuronic acid was investigated, and the results indicated significant inter-species differences in the rate of glucuronidation, which was saturable at low concentrations in all species tested, except pigs. The significant differences between the percentages of glucuronidation of ZEA, alpha-ZOL, and beta-ZOL suggest not only differences in the affinity of the individual substrate, but might also indicate the presence of different isoforms of uridine diphosphate glucuronyl transferases (UDPGTs). The results are of clinical relevance, as they contribute to the understanding of the species-specific susceptibility towards exposure to ZEA.
玉米赤霉烯酮（ZEA）是一种镰刀菌毒素，在动物饲料原料中经常被发现。已知它在所有受试动物中都会产生雌激素效应，但不同物种的易感性有所不同，这可能反映了ZEA代谢过程的差异，其主要代谢过程涉及羟基化反应，推测由3α-和3β-羟基类固醇脱氢酶催化，以及与葡萄糖醛酸结合。在本研究中，研究了各种家畜肝脏亚细胞组分对ZEA的生物转化，并与大鼠进行了比较。在不同亚细胞组分中，确定了绝对和相对代谢产物生成速率方面显著的种间差异。猪肝脏微粒体产生的α-玉米赤霉醇（α-ZOL）量最高（V(max)=795.8±122.7pmol/mg/min），而在鸡微粒体中可测得最高量的β-玉米赤霉醇（β-ZOL）（V(max)=1524±29.7pmol/mg/min）。除绵羊和牛外，微粒体组分中α-ZOL的生成效率（以表观V(max)/k(m)的比值表示）高于线粒体后组分。相反，β-ZOL的表观生成效率在猪、牛、鸡和大鼠中较高，但在绵羊中非常低。研究了ZEA与葡萄糖醛酸的结合，结果表明葡萄糖醛酸化速率存在显著的种间差异，除猪外，所有受试物种在低浓度下葡萄糖醛酸化均具有饱和性。ZEA、α-ZOL和β-ZOL葡萄糖醛酸化百分比之间的显著差异不仅表明各个底物的亲和力不同，还可能表明存在不同的尿苷二磷酸葡萄糖醛酸转移酶（UDPGTs）同工型。这些结果具有临床相关性，因为它们有助于理解物种对ZEA暴露的特异性易感性。
