ALCOHOL METABOLISRN IN DROSOPHILA: ITS RELEVANCE IN NUTRITION AND DETOXIFICATION

Abstract

Alcohol rnetabolism in Drosophila has recently attracted a lot of interest probably due to the essentiai role that the enzyme alcohol dehydrogenase plays in alcohol transforrnation. Species differ markedly in alcohol tolerance and this is attributed to ADH. While some species can cope with high ethanol concentrations (28%), others do not survive when reared in rninimal amounts (0'9%). Most of the species belong to an interrnediate group being able to tolerate and rnake use of alcohols produced in ferrnenting fruits which frequently constitute their natural habitats, al least during embryonic and larval developrnent. The analysis of ethanol metabolisrn and other primary alcohols, will help to establish not only the biochernical transformations, the enzyrnes involved and the relationships between other rnetabolic pathways but also to clarify the various factors relevant to the species adaptation towards alcohol-rich or rnoderately rich environrnents. Different types of evidence seern to indicate that one of these key factors is clearly ADH. In its absence, species become extremely sensitive to ethanol. Yet, it is still unclear which enzyrne features account for higher ethanol tolerance. Avalaible data suggest that the kinetic coeficient Vrnax and the quantity of enzyrne synthesized could be the rnost relevant factors in alcohol adaptation. On the other hand, kinetic and structurai studies of ADH reveal that ethanol utilization probably represents a recent evolutionary acquisition and was not associated initially with the enzyrne. Other enzyrnatic systerns help Drosophila in the exploitation of alcohol-rich environments, although they only account for sorne 10% of alcohol utilization. Aldehydes produced are further oxidized to carboxilic acids and this seems to be produced by an aldehyde dehydrogenase (ALDH), recently characterized in Drosophila, which shares relevant biochemical properties with liver ALDH. Ethanol is then eventually transforrned to acetic acid and acetylCoA which may serve as substrate for fatty acid synthesis or be oxidized in the Krebs cycle. All appears to be different when ADH acts on secondary alcohols. Highly toxic, rnetabolically inert compounds are produced which at the sarne time inactivate the enzyrne. Nevertheless, ADH shows lowest Km values with these substrates. sornething that cannot be easily explained, at least in biological terrns. It has been clairned that greater affínity could be due to the type of chernical interaction between the substrate and the active site of the enzyrne. Studies have also been carried out to know the effect of ethanol and 1 or sucrose in alcohol rnetabolisrn to approach the real situation that Drosophila encounters in natural habitats. It has been proved that ethanol and sucrose, together or individually, exert a positive regulation on ADH activity. It is not clear what produces this effect: increased levels of synthesis of the enzyme, lower turnover rate, re-activation of preexisting less active molecular forrns or if it is directly produced by these compounds or its metabolic interrnediates. The positive regulatory effect of ethanol and sucrose combined only appears if sucrose concentration does not reach a threshold level, when this is exceeded, a negative effect would be produced. When sucrose, at permisible amounts under the inhibitory effect, is supplernented to an ethanol diet, positive rnetabolic regulation is also observed in the activities of lipogenic enzyrnes together with an increase in the triacylglycerol content. Other type of data seem to strenghten the view that ADH role in alcohol transfonnation is not necessarily related to its possible function in intermediary metabolism. Among these are the facts that in the absence of ethanol ADH-negative mutarits differ from wild-type individuals in these metabolic pathways and that sucrose done can modulate ADH activity. In Drosophila , a clear picture of the relationships between catabolic and anabolic pathways has not yet emerged and this also applies to individual pathways. Alcohol metabolism is a clear example: it is not known how the activities of enzymes involved in this process are regulated and if this is acchieved through a direct or indirect effect. Until this stage is reached much of the meaning of the experimental results will be difficult to grasp. Obviously, there is a long way to go before there will be an amount of data comparabre toother organisms, as is the case of mammals, frequently investigated because they serve as model systems for humans.