KYNURENINE HYDROXYLASE - A POTENTIAL RATE-LIMITING ENZYME IN TRYPTOPHAN-METABOLISM
KYNURENINE HYDROXYLASE - A POTENTIAL RATE-LIMITING ENZYME IN TRYPTOPHAN-METABOLISM
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DOI：
10.1042/bst0130441
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发表时间：
1985-01-01
影响因子：
3.9
通讯作者：
MCCREANOR, GM
中科院分区：
文献类型：
--
作者：
BENDER, DA;MCCREANOR, GM
犬尿氨酸羟化酶活性在甲状腺功能亢进症中明显降低。对大鼠给予甲状腺素导致在几天内下降至对照活性的50%。这反映在K/HK比率从2.6变为22.2。在停止激素时，酶逐渐恢复，并恢复到对照K/HK比率。色氨酸氧化代谢的这种抑制导致烟酰胺核苷酸的从头合成的显著减少和辅酶的组织浓度的降低（Okamoto等人，1971年）。饮食中过量的亮氨酸与烟酸缺乏病糙皮病的病因有关（Gopalan和Srikantia，1960）。Magboul & Bender（1983）已经证实，饮食中相对过量的亮氨酸抑制大鼠从色氨酸合成NAD（P）。可能涉及许多因素，包括：犬尿氨酸和色氨酸之间的竞争以摄取到组织中;吡啶甲酸羧化酶的活性增加（Bender，1983）和亮氨酸对犬尿氨酸酶的抑制以及a-氧代异己酸（亮氨酸的0x 0酸）对犬尿氨酸羟化酶的抑制（Magbod& Bender，1983）。这最后一点在生理上不太可能有重要意义。α-氧代异己酸盐对犬尿氨酸羟化酶的抑制主要是非竞争性的，Ki为63 k18 m-1（DA Bender，未发表的工作），而α-氧代异己酸盐的组织浓度通常不会升高到5- 10 p-1以上（Hutson和哈珀，1981）。即使喂食高亮氨酸饮食也不太可能引起α-氧代异己酸的充分积累以显著抑制犬尿氨酸羟化酶。许多研究表明，女性糙皮病的发病率是男性的两倍（米勒，1978）。一个重要的因素可能是雌激素代谢物对犬尿氨酸酶的抑制（Bender & Wynick，198 1）。此外，Bender和Totoe（1984）已经表明，在接受硫酸雌酮（15 mg/kg饮食，大约相当于绝经期激素替代疗法中使用的剂量）的卵巢切除大鼠中，肝脏中犬尿氨酸羟化酶的活性降低至对照动物中的30%。在这些条件下，犬尿氨酸羟化酶的活性肯定低于色氨酸氧化代谢的任何其他酶的活性;雌激素治疗的大鼠具有较低的烟酰胺核苷酸组织浓度和较低的NAD（P）代谢的终产物NL-甲基烟酰胺排泄。雌激素的这种作用机制尚不清楚。在体外加入最多1毫雌酮硫酸盐、雌二醇或乙炔雌二醇对羟化酶的活性没有影响，但在向卵巢切除大鼠腹膜内注射乙炔雌二醇12小时内羟化酶活性的变化是明显的（DA Bender & J.- F.内源性雌激素也可能影响犬尿氨酸羟化酶。艾尔·佐格比（1978 a）显示，青春期前女孩的K/HK自发排泄为0.5，而23 - 40岁女性的比值为4.7，绝经后女性为1.4。色氨酸加氧酶的活性是限制色氨酸进入导致不可逆氧化催化剂的途径以及从体内去除色氨酸的因素。然而，当代谢物通过氧化途径的通量增加时，如皮质类固醇激素诱导色氨酸加氧酶或给予负荷剂量的色氨酸后，或者当犬尿氨酸羟化酶受到中度抑制时，犬尿氨酸的羟基化可能会限制色氨酸代谢物向前代谢的速率。
Kynurenine hydroxylase activity is markedly reduced in hyperthyroidism. The administration of thyroxine to rats results in a fall to 50% of the control activity over several days. This is reflected in a change in the K/HK ratio from 2.6 to 22.2. On withdrawal of the hormone there is a gradual recovery of the enzyme, and a return to the control K/HK ratio. This inhibition of tryptophan oxidative metabolism results in a significant reduction in the synthesis de nouo of nicotinamide nucleotides and a reduction in tissue concentrations of the coenzymes (Okamoto et al., 1971). A dietary excess of leucine has been implicated in the aetiology of the niacin-deficiency disease, pellagra (Gopalan & Srikantia, 1960). Magboul & Bender (1983) have confirmed that a relative excess of leucine in the diet inhibits the synthesis of NAD (P) from tryptophan in rats. A number of factors may be involved, including: competition between kynurenine and tryptophan for uptake into tissues; increased activity of picolinate carboxylase (Bender, 1983) and inhibition of kynureninase by leucine and of kynurenine hydroxylase by a-oxoisocaproate, the 0x0 acid of leucine (Magbod& Bender, 1983). This last is unlikely to be physiologically important. The inhibition of kynurenine hydroxylase by a-oxoisocaproate is mainly non-competitive, with a K, of 63 k 1 8 m~(DA Bender, unpublished work), while tissue concentrations of a-oxoisocaproate do not normally rise above 5-1Op~(Hutson & Harper, 1981). Even feeding a high-leucine diet is unlikely to cause a sufficient accumulation of a-oxoisocaproate to give significant inhibition of kynurenine hydroxylase. A number of studies have shown that the incidence of pellagra is twice as high in women as in men (Miller, 1978). An important factor may be inhibition of kynureninase by oestrogen metabolites (Bender & Wynick, 198 1). Additionally, Bender & Totoe (1984) have shown that in ovariectomized rats receiving oestrone sulphate (1 5 mg/kg of diet, approximately equivalent to doses used in menopausal hormone replacement therapy), the activity of kynurenine hydroxylase in the liver is reduced to 30% of that in control animals. Under these conditions, the activity of kynurenine hydroxylase is certainly lower than that of any other enzyme of tryptophan oxidative metabolism; oestrogen-treated rats have lower tissue concentrations of nicotinamide nucleotides and lower excretion of NL-methylnicotinamide, the end product of NAD (P) metabolism. The mechanism of this action of oestrogens is not clear. The addition of up to 1 mwoestrone sulphate, oestradiol or ethynyloestradiol in vitro has no effect on the activity of the hydroxylase, yet changes in hydroxylase activity are apparent within 12 h of the intraperitoneal injection of ethynyloestradiol into ovariectomized rats (DA Bender & J.-F. Bowden, unpublished work).Endogenous oestrogens may also affect kynurenine hydroxylase. El-Zoghby at al.(1978a) showed that the spontaneous excretion of K/HK was 0.5 in pre-pubertal girls, while in women aged between 23 and 40 years the ratio was 4.7, and in post-menopausal women it was 1.4. The activity of tryptophan oxygenase is the limiting factor for the entry of tryptophan into the pathway that leads to irreversible oxidative catabolism, and the removal of tryptophan from the body. Nevertheless, it is likely that when the flux of metabolites through the oxidative pathway is increased, as after induction of tryptophan oxygenase by corticosteroid hormones or the administration of a loading dose of tryptophan, or when kynurenine hydroxylase is moderately inhibited, the hydroxylation of kynurenine becomes rate-limiting for the onward metabolism of tryptophan metabolites to …