Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss

Abstract

An imbalance between phase I drug metabolizing enzymes and phase II detoxification enzymes may contribute to the development of pre-eclampsia. Polymorphic variants in the phase I enzyme, cytochrome P450 genes may lead to increased toxification, whereas polymorphisms in the phase II enzyme, glutathione S-transferase genes may result in impaired detoxification. Most abundant in placenta and decidua is glutathione S-transferase P1-1, which may therefore be of particular importance in reproduction. We studied the frequencies of polymorphic variants in those enzymes in 187 women with recurrent early pregnancy loss and in 109 women with an uncomplicated obstetric history. DNA was extracted and subsequently polymerase chain reaction based genotyping assays were used. chi(2)-Analysis and Fisher's exact test were used for statistical evaluation. The glutathione S-transferase P1b-1b genotype was found significantly more often in women with recurrent early pregnancy loss than in controls (12% versus 5%, P = 0.03), in particular in those who consumed coffee (P = 0.02) or smoked cigarettes (P = 0.04). Polymorphisms in other glutathione S-transferase and cytochrome P450 genes occurred equally frequently in cases and controls. In conclusion, the occurrence of the glutathione S-transferase P1b-1b genotype, leading to lower glutathione S-transferase Pi enzyme activity and consequently to impaired placental detoxification, may represent a risk factor for recurrent early pregnancy loss.

Glutathione S-transferase A1 polymorphism and the risk of recurrent spontaneous abortion in Chinese Han population

“…Thus, compared to non-pregnancy women, pregnancy women is in a state of high oxidative load. The genetic variants in metabolic detoxification activities could provoke the imbalance between the interactions of phase Iand II biotransformation enzymes, as a result, increased exposure of conceptus to endo-and exogenous toxins might contribute to the development of RSA [12].…”

“…GSTs are divided into three families: cytosolic, mitochondrial, and the membrane-associated proteins in eicosanoid and glutathione metabolism proteins, among them, the cytosolic subfamily is by far the most abundant one [7]. Numbers of studies have suggested that the genetic polymorphism of cytosolic GST genes was associated with the risk of RSA [8][9][10][11][12].…”

Comparison between Essential Hypertension and Pregnancy-induced Hypertension: a Genetic Perspective

“…More recently, it has been theorized that an abnormal placenta formation is involved in increases in thrombus diseases, and thus, may cause PIH. Therefore, thrombus factors such as the Leiden mutation of coagulation factor V (F5) and Detoxification Glutathione S-transferase (GSTP1) GSTP1 1b-1b genotype Dutch [67] In recent decades, women with pregnancy hypertension were instructed to restrict their dietary intake and strictly monitor salt intake, depending on severity, and many patients blamed themselves for developing pregnancy hypertension. However, it has been clarified that dietary and salt-intake restrictions need to be reexamined.…”

The Association of Early Pregnancy Loss with Polymorphism in Xenobiotics Detoxification Genes

“…It is known that low functional activity of glutathione S-transferases is associated with preeclampsia risk increase. Furthermore, many investigations demonstrated the association between mutant allele and genotype frequencies and severity index, for example with increased platelet aggregation (Zusterzeel et al, 2000a).…”

“…Data on the association of CYP1A1 and GSTP1 gene polymorphism with pregnancy loss risk increase are controversial (Zusterzeel et al, 2000a;Suryanarayana et al, 2004). Data on the alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism effect on pregnancy loss risk are very poor.…”