Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels.
Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels.
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DOI：
10.1152/ajprenal.00171.2007
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发表时间：
2007-08
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通讯作者：
V. Vitvitsky;A. Prudova;S. Stabler;S. Dayal;S. Lentz;R. Banerjee
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作者：
V. Vitvitsky;A. Prudova;S. Stabler;S. Dayal;S. Lentz;R. Banerjee
血浆总同型半胱氨酸（tHcy）升高是缺血性心脏病和卒中的独立危险因素。流行病学研究表明，男性的tHcy水平高于女性，但这种性别依赖性差异的机制尚不清楚。同型半胱氨酸的细胞内处置的一种途径是由胱硫醚β-合酶（CBS）催化。肾功能是已知的tHcy的一个重要的决定因素，在这项研究中，我们证明，肾CBS的表达和活性在小鼠去势后减少约两倍，而卵巢切除术是没有影响。男性肾脏CBS活性较高（22.7 +/- 3.1 mmol胱硫醚.h（-1）.kg肾脏（-1））与雌性（8.4 +/- 3.4 mmol胱硫醚.h（-1）.kg肾（-1），P <或= 10（-6））与雄性比雌性更低的血浆tHcy水平相关，并且这种差异在Cbs+/-小鼠中加剧（雄性7.7 +/- 1.9 μ mol/l对雌性13.8 +/- 6.4 μ mol/l，P = 0.005）。令人惊讶的是，哺乳动物对肾CBS表现出多种调节模式，雌性在小鼠中表现出较低的CBS活性，在大鼠和人类中表现出较高的CBS活性，并且在兔、仓鼠和豚鼠中与雄性难以区分。我们的数据表明，睾丸激素依赖性调节人类CBS在肾脏中可能有助于同型半胱氨酸转硫的性别依赖性差异。
Elevated plasma total homocysteine (tHcy) is an independent risk factor for ischemic heart disease and stroke. Epidemiological studies reveal that men have higher tHcy levels than women, but the mechanism underlying this sex-dependent difference is unknown. One route for intracellular disposal of homocysteine is catalyzed by cystathionine beta-synthase (CBS). Renal function is known to be an important determinant of tHcy, and, in this study, we demonstrate that renal CBS expression and activity in mice diminished approximately twofold after castration, whereas ovariectomization was without effect. The higher renal CBS activity in males (22.7 +/- 3.1 mmol cystathionine.h(-1).kg kidney(-1)) vs. females (8.4 +/- 3.4 mmol cystathionine.h(-1).kg kidney(-1), P < or = 10(-6)) in C57Bl/6J mice was associated with lower plasma tHcy levels in males vs. females, and this difference was exacerbated in Cbs+/- mice (7.7 +/- 1.9 micromol/l in males vs. 13.8 +/- 6.4 micromol/l in females, P = 0.005). Surprisingly, mammals exhibit a diversity of regulatory patterns for kidney CBS, with females exhibiting lower CBS activity in mice, higher in rats and humans, and being indistinguishable from males in rabbit, hamster, and guinea pig. Our data suggest that testosterone-dependent regulation of human CBS in kidney may contribute to sex-dependent differences in homocysteine transsulfuration.