HEPATIC HYDROXYLATION OF MELATONIN IN THE RAT IS INDUCED BY PHENOBARBITAL AND 7,12-DIMETHYLBENZ[A]ANTHRACENE - IMPLICATIONS FOR CANCER ETIOLOGY

The protective function of the pineal hormone melatonin in the etiolog y of cancer and carcinogenic activation is increasingly well-establish ed. Low melatonin levels seem to parallel cancer growth. The question arises as to which factors cause the depression of melatonin levels an d what the direct effects are. Melatonin is known to be metabolized in the liver by hydroxylation and subsequent conjugation yielding 6-sulf atoxymelatonin as a main product. Nevertheless, the microsomal monoxyg enases catalyzing the first step have been poorly investigated. To fur ther characterize these enzymes, typical inducers of three different s ub-classes, namely phenobarbital, 7,12-dimethylbenz[a]anthracene, and 17 beta-estradiol, were administered to female Fischer rats. Circadian urinary excretion patterns of melatonin and 6-sulfatoxymelatonin were determined over a 24-hour period on the third (second) day of inducti on. Liver homogenates were used to monitor the in vitro conversion of melatonin or 6-hydroxymelatonin to 6-sulfatoxymelatonin. Results of bo th approaches showed the microsomal monoxygenases catalyzing the 6-hyd roxylation of melatonin to be strongly inducible by phenobarbital and to a lesser degree by the polyaromatic hydrocarbon 7,12-dimethylbenz[a ]anthracene. The dramatic depletion of circulating melatonin as a resu lt of these induction patterns and its possible implications for oncog enesis are discussed.