This study was aimed at the estimation of water pollution with heavy metals using four biomarkers as well as to study the species-site interaction. Two species of tilapia as well as two catfish species caught from four sites that represent differential environmental stresses were used for this purpose. Water samples and gills were analyzed for heavy metal contents. Three enzyme biomarkers (acid phosphatase (AP), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), metalothionein (MT) gene expression) as well as real time PCR quantification of metalothionein transcripts from liver were used to monitor fish response to water pollutants. Results showed various activities of the four biomarkers at the different studied sites. There were clear interaction between fish species and the level of heavy metals. Real time PCR evaluation of metalothionein gene expression revealed species variations at similar sites. It is concluded that there are various types of interaction of species at different sites. These types of interaction depend on the type of biomarker tested.