Vitae (Sep 2005)
MODELO QSAR PARA LA PREDICCIÓN DE LOS TIEMPOS DE VIDA MEDIA DE BIFENILOS POLICLORADOS EN HUMANOS QSAR MODEL FOR THE PREDICTION OF THE HALF LIFE OF POLYCHLORINATED BIPHENYLS IN HUMANS
Abstract
La velocidad con que los bifenilos policlorados (PCBs) son eliminados en humanos, representada por sus períodos de vida media (t1/2), es de gran relevancia ambiental. En este trabajo, a partir de datos reportados en la literatura, se elabora una base de datos de esta variable tóxico-cinética de PCBs en humanos. 14 estructuras de PCBs son optimizadas energéticamente, haciendo previamente un barrido del ángulo diedro entre sus anillos fenilícos , utilizando AM1 para encontrar la conformación más estable. Los PCBs mono-orto sustituidos presentan un ángulo diedro aproximado de 120° y los poli-orto sustituidos de 90°. A partir de las estructuras optimizadas se calculan diversos descriptores moleculares, empleando el método B3LYP/6-31G**. Los descriptores son asociados con los t1/2 mediante análisis de regresión lineal múltiple. Este análisis revela que el t1/2 de PCBs es función de la sumatoria de cargas de átomos de cloro (ΣQCl) y el valor total de cargas de carbonos en posición meta (ΣQC-meta). El coeficiente de regresión es de 0.84 y PThe elimination rate of the polychlorinated biphenyls (PCBs) in humans is of great environmental importance, as represented by their half-lives (t1/2). Based on the literature, a database of this toxickinetic variable for PCBs in humans is elaborated. 14 PCB structures with known half-lives are optimized, making a previous scan of the dihedral angle between the two phenyl rings, using AM1 to find the most stable conformation. Substituted mono-orto PCBs present an approximate dihedral angle of 120°, and the substituted poly-orto of 90°. Several descriptors are calculated from optimized structures using B3LYP/6-31G**. The molecular descriptors are associated with the t1/2 values by multiple lineal regression analysis. This reveals that the t1/2 of PCBs is a function of the sum of atomic charges on the chlorine atoms (ΣQCl) and the sum of atomic charges for the carbon atoms in meta position (ΣQC-meta). The regression coefficient value of the prediction model is 0.84, and the Pvalue is <0.01 (range: 1.2-24 years). A discriminant analysis allows to verify the molecular characteristics that describe best the t1/2 of PCBs. The discrimination function carried out for two groups, finds that the descriptor ΣQC-meta is the most important to classify the PCBs according to their t1/2. Taking in account that the metabolism of PCBs depends on the substitution of the carbon atoms in meta-para positions, since this begins with the formation of an epoxy-PCB in these atoms of the biphenyls, the electronic descriptor ΣQC-meta can explain this local chemical environment and the metabolic susceptibility of the congener to degradation by cytochrome P450 isozymes (CYPs).
