Cellular and molecular mechanisms of alcohol-induced osteopenia

Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a 14CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p less than 0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a¹⁴CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p<0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Temperature-dependence of stress-induced hepatic autophagy

Summary In rats, restraint for 48 h elicits hepatic glycogen depletion, autophagy and other ultrastructural changes (e.g. mitochondrial enlargement and rough endoplasmic reticulum disorganization) associated with marked hypothermia. By restoring the body temperature of these animals, all the hepatocytic alterations are abolished.Supported in part by the Medical Research Council of Canada (Block Term Grant MT-1829) and the Conseil de la recherche en santé du Québec. A preliminary report of this work was presented at the 19th Annual Meeting of the Canadian Federation of Biological Societies, Halifax, 15–18 June 1976.Recipient of a studentship from the Conseil de la recherche en santé du Québec.The authors thank Mr M. Audet, Mrs A. Perea and Miss F. Dionne, for their excellent technical assistance.     

Lipid peroxidation in dietary liver necrosis

Zusammenfassung Es wird festgestellt, dass der Einfluss von Lipidperoxyden nicht für die Entstehung gewisser Formen der Lebernekrose verantwortlich gemacht werden können.

---

---

Acknowledgments. The authors wish to thank Dr.A. K. Ghoshal for many valuable discussions.     

Survival of stressed rats following experimental cardiac necrosis

Résumé Une nécrose myocardique a été produite chez. le rat mâle adulte avec de l'isoprotérénol. Aucune différence de survie significative n'a été constatée entre les individus traités et les non traités lorsque les uns et les autres ont été soumis à l'hypoxémie, la nage forcée dans l'eau froide, ou la restriction par attache.

---

---

This work was conducted in the Department of Chemical Pharmacology. We wish to thank Dr.D. A. Buyske for his interest and suggestions.     

Cyclophosphamide-impaired regulation of hepatic heme metabolism

In male rats hepatic cytochromes b5 and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a 'non-cytochromal' form. Parallel to the above changes the heme metabolism showed derangement: delta-aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.     

The reticulo-endothelial localization of hepatic acetylcholinesterase

Zusammenfassung Die Acetylcholinesterase wurde histochemisch in den sinusoidal-reticulo-endothelialen Zellen der Kaninchenleber gefunden. Es wird angenommen, dass das Enzym an der Fett- und Esterumwandlung beteiligt ist.     

Chlorinated benzene induction of hepatic porphyria

Summary 1,4-Dichlorobenzene and 1,2,4-trichlorobenzene were compared with hexachlorobenzene which is known to cause porphyria. Although hexachlorobenzene administration resulted in a manyfold increase in liver porphyrin levels and urinary excretion of porphyrins, the lesser chlorinated compounds did not do so.Supported by grant R804328 from the US Environmental Protection Agency.     

Cyclophosphamide-impaired regulation of hepatic heme metabolism

Summary Im male rats hepatic cytochromes b₅ and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a non-cytochromal form. Parallel to the above changes the heme metabolism showed derangement: -aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.     

Brominated benzene induction of hepatic porphyria

Summary Unlike the highly porphyrinogenic fungicide hexachlorobenzene, hexabromobenzene was a poor inducer of porphyria. Similarly, 1,2-dibromobenzene and 1,2,4-tribromobenzene, while causing small increases in hepatic porphyrins, did not increase ALA synthetase or the urinary excretion of porphobilinogen (PBG), aminolevulinic acid (ALA) or porphyrins.Supported by grant R805070 from the US Environmental Protection Agency.     

Mucopolysaccharides in experimental hepatic fibrosis

Résumé L'intoxication chronique au tétrachlorure de carbone produit dans le tissu hépatique du rat une forte augmentation des hexosamines et des sulfates liés sans modifier la teneur en acides uroniques. Ces modifications sont parallèles au processus de fibrilogénèse. Ces données indiquent l'accumulation pathologique d'un matériel de type glycosaminoglycan sulfaté.     

Myofibroblasts in hepatic schistosomal fibrosis

Summary Myofibroblasts were identified in liver portal spaces of patients with Symmers' fibrosis following infection by Schistosoma mansoni.Acknowledgments. This research was supported by a grant from U.E.R. (Human Biology) Claude Bernard University, Lyon (France), and by the Conselho Nacional de Pesquisas (Brazil). Thanks are due to Mrs Pavans de Ceccatty for her skillful technical assistance.