Vitvitsky Victor, Prudova Anna, Stabler Sally, Dayal Sanjana, Lentz Steven R, Banerjee Ruma
Redox Biology Center and the Biochemistry Dept., University of Nebraska, Lincoln, NE 68588-0664, USA.
Am J Physiol Renal Physiol. 2007 Aug;293(2):F594-600. doi: 10.1152/ajprenal.00171.2007. Epub 2007 May 30.
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.
血浆总同型半胱氨酸（tHcy）升高是缺血性心脏病和中风的独立危险因素。流行病学研究表明，男性的tHcy水平高于女性，但其性别差异的潜在机制尚不清楚。同型半胱氨酸在细胞内的一种代谢途径由胱硫醚β-合酶（CBS）催化。已知肾功能是tHcy的重要决定因素，在本研究中，我们证明小鼠去势后肾脏CBS的表达和活性降低了约两倍，而卵巢切除则没有影响。在C57Bl/6J小鼠中，雄性肾脏CBS活性较高（22.7±3.1 mmol胱硫醚·h⁻¹·kg肾脏⁻¹），而雌性较低（8.4±3.4 mmol胱硫醚·h⁻¹·kg肾脏⁻¹，P≤10⁻⁶），这与雄性血浆tHcy水平低于雌性有关，并且这种差异在Cbs+/-小鼠中更为明显（雄性为7.7±1.9 μmol/L，雌性为13.8±6.4 μmol/L，P = 0.005）。令人惊讶的是，哺乳动物对肾脏CBS表现出多种调节模式，雌性在小鼠中CBS活性较低，在大鼠和人类中较高，而在兔子、仓鼠和豚鼠中与雄性无差异。我们的数据表明，睾酮对人肾脏CBS的依赖性调节可能导致同型半胱氨酸转硫途径的性别差异。
