Hexachlorobenzene-induced alterations on neutral and acidic sphingomyelinases and serine palmitoyltransferase activities. A time course study in two strains of rats.
Hexachlorobenzene (HCB) induces porphyria both in humans and rodents, and hepatocarcinoma in rodents. In a previous work we observed that HCB produces a continuous decrease in hepatic sphingomyelin (SM) content in Wistar rats. A distinguishing characteristic of sphingolipids breakdown products is their participation in anti-proliferative and apoptotic processes and in the suppression of oncogenesis. As a first step to elucidate the role of SM decrease in the hepatotoxicity induced by HCB, the present study evaluates the metabolic causes of the continuous decrease in hepatic SM content observed in Wistar rats with HCB intoxication, and its relation with porphyria development. For this purpose, the time-course (3, 7, 15, 21 and 28 days) of the effects of HCB on hepatic SM levels and on some of the enzymes of SM synthesis (serine palmitoyltransferase, SPT) and catabolism (sphingomyelinases, SMases) was followed, using two strains of rats differing in their susceptibility to acquire porphyria: Chbb THOM (low) and Wistar (high). HCB (1 g kg(-1) b.w. per day) was administered by gastric intubation as an aqueous suspension. After 5 days of HCB treatment, animals were allowed a 2-day recovery period without HCB administration. Two phases in the HCB-induced damages to sphingolipid metabolism were observed. The first stage (7 days of treatment), common to both strains of rats, was characterized by a decrease in hepatic SM levels (17-25%) and in SPT activity (50-43%), while strain differences were found for the later stage. In Chbb THOM rats, hepatic SM content was restored to normal values concomitantly with an increase in SPT activity (44%, at day 28), and without any increase in SM catabolism. In addition, the level of the other phospholipids was not altered. In Wistar rats, hepatic SM levels decreased continuously throughout the experiment, accompanied by increases in SPT, acidic sphingomyelinase (A-SMase) and neutral sphingomyelinase (N-SMase) activities (86, 28.5 and 78% increase, respectively). A role for glutathione (GSH) in the interstrain differences or a direct effect of HCB on SM metabolism was not found. The present study: (a) demonstrates that N-SMase, A-SMase, and SPT are some of the enzymes that play a role in the HCB-induced decrease of hepatic SM content; (b) finds that HCB-induced alterations of SM metabolism do not correlate with HCB-induced accumulation of hepatic porphyrins; and (c) proposes a link between HCB-induced alterations in phospholipid pattern and in SM metabolism. The increased SM hydrolysis produced as a consequence of SMases induction could be regarded as a cellular response to liver injury elicited by HCB, perhaps acting through the activation of SM signal transduction pathway delaying the proliferative processes observed after long-term treatment with HCB in some rodent species. However, such protective mechanism appears to be strain-dependent.
Billi de Catabbi
S C
SC
Departamento de Química Biológica, Laboratorio de Porfirias Experimentales y Metabolismo del Hemo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II. 4to piso, 1428 Buenos Aires, Argentina.
Setton-Advruj
C P
CP
Sterin-Speziale
N
N
San Martín de Viale
L C
LC
Cochón
A C
AC
D000217:Acyltransferases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051102:Serine C-Palmitoyltransferase; D013045:Species Specificity; D013108:Sphingomyelin Phosphodiesterase / Q000187:drug effects* / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013997:Time Factors
D005659:Fungicides, Industrial; D010743:Phospholipids; D011166:Porphyrins; D013109:Sphingomyelins; D006581:Hexachlorobenzene; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione