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RMI 12330 A [ N -( cis -2-phenlcyyclopentyl) azacyclotridecan-2-imine hydrochloride] inhibits choleratoxin-induced intestinal hypersecretion, presumably via an inhibition of the mucosal enzyme adenylate cyclase. We previously reported the inhibition by RMI 12330 A of the adenylate cyclase activity from rat liver plasma membrane preparations. We firstly extend here these results, showing the inhibition by RMI 12330 A of adenylate cyclase activity from spleen, brain, heart and kidney. Furthermore, in plasma membrane preparations, this agent inhibited the activities of Mg 2+ -ATPase and leucyl-β-naphthylamidase but had no effect upon 5′nucleotidase. In non-activated rat liver microsomes, the activities of p -nitrophenol and bilirubin UDP-glucuronosyltransferases, and of glucose-6-phosphatase, were enhanced by low concentrations of RMI 12330 A but inhibited by higher concentrations. This biphasic effect disappeared when digitonin-activated or Emulgen 911-solubilized microsomal membranes were used. Thus, RMI 12330 A does not behave as a specific inhibitor of adenylate cyclase, since it also perturbs other membrane-associated enzyme activities.

Two groups of female Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing 36 per cent of total calories as ethanol or additional carbohydrate (controls). One group was fed a high fat diet (35 per cent of total calories as fat); the other group was fed a low fat diet (2 per cent of total calories as linoleate as the only source of fat). When given with the high fat diet, ethanol increased cytochrome P-450 and microsomal phospholipid content per g of liver. When given with a low fat diet, it increased cytochrome P-450 to a lesser extent and did not alter the microsomal phospholipid content when expressed per g of liver or per 100 g of body weight. Phosphatidylcholine accounted for the greater porportion of phospholipids and was increased by ethanol only with the high fat diet. L -Methionine-methyl[ 3 H] and [ 14 C]choline incorporation into phosphatidylcholine was unaltered by ethanol in either model. The fatty acid composition of phosphatidylcholine was altered by ethanol more significantly with the high fat diet. Since ethanol similarly enhances the activity of benzphetamine demethylation in both dietary models, quantitative and qualitative differences in microsomal phospholipids produced by ethanol are probably not responsible for the induction by ethanol of this drug-metabolizing enzyme activity. Further evidence to that effect was obtained from the measurement of benzphetamine demethylation in vitro by partially purified cytochrome P-450, reductase and lipid fractions of ethanol-fed and control rats fed a high fat diet. The stimulation of benzphetamine demethylation by the lipid fraction was identical whether using lipids from microsomes of ethanol-fed animals or control animals. Dietary fat plays a role in the induction by ethanol of cytochrome P-450 and NADPH-cytochrome P-450 reductase and on microsomal phospholipid content and composition. The effects of ethanol on microsomal phospholipids are probably not related to the induction of benzphetamine demethylation activity.