Necrogenic Action of Carbon Tetrachloride in the Rat: A Speculative Mechanism Based on Activation

Slater, T. F.

doi:10.1038/209036a0

Cited by 436 publications

(126 citation statements)

References 26 publications

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“…In a later stage or with a larger dose of CCl4, however, a considerable decrease of the activity is reported (25,28,29). According ly, the decrease of microsomal glucose-6-phosphatase activity in viva may be produced by CCl4 per se as well as its more toxic metabolite as suggested by other workers (20,21,30).…”

Section: Discussionmentioning

confidence: 80%

“…Although an exact mechanism involved in the CCl4-induced liver damage has yet to be established, it seems quite certain that CC14 acts directly on the liver (18)(19)(20). It has been suggested that an attack point of CC14 is the endoplasmic reticulum of liver cells (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that an attack point of CC14 is the endoplasmic reticulum of liver cells (20,21).…”

Section: Discussionmentioning

confidence: 99%

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STUDIES ON THE FUNCTION OF CELL MEMBRANE 10th REPORT :EFFECTS OF CCl4 ON THE MARKER ENZYME ACTIVITIES AND FINE STRUCTURES OF RAT LIVER PLASMA MEMBRANES AND MICROSOMES IN VITRO

Masuda

Yano

Sumida

et al. 1975

Japanese Journal of Pharmacology

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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STUDIES ON THE FUNCTION OF CELL MEMBRANE 10th REPORT :EFFECTS OF CCl4 ON THE MARKER ENZYME ACTIVITIES AND FINE STRUCTURES OF RAT LIVER PLASMA MEMBRANES AND MICROSOMES IN VITRO

Masuda

Yano

Sumida

et al. 1975

Japanese Journal of Pharmacology

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“…1 and 2). There is good evidence that CC14, like DMBA, requires activation by the microsomal enzyme systems of the liver before it exerts a toxic effect (see Recknagel and Ghoshal, 1966;Slater, 1966;Garner and McLean, 1969). The most logical explanation for the reciprocal relationship between liver damage/adrenal protection and adrenal damage/liver protection is that both toxins are activated by the same or similar enzyme systems in the liver and are mutually exclusive when given at short intervals apart.…”

Section: Ccl4mentioning

confidence: 99%

Reciprocal Relationship Between the Production of Adrenal Damage by 7,12-Dimethylbenz(a)anthracene in Rats and the Induction of Liver Damage by Various Treatments

Wheatley¹,

Gerrard²,

Kernohan³

et al. 1972

Br J Cancer

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Summary.-Further investigations into the mechanism by which CC14 administration to Sprague-Dawley rats protects them against the adrenocorticolytic action of dimethylbenz(a)anthracene (DMBA) are reported. The results show that CC14 must be given shortly before DMBA to achieve the best protection and that treatments given after DMBA are ineffective. It was established that the hepatotoxicity of CCI4 in these experiments was related reciprocally to the adrenocorticolytic effect of DMBA.Protection with butter yellow (DAB) was achieved only when sufficient time elapses for drug metabolism to be stimulated in the liver. Butter yellow given after DMBA has no protective effect but the prior exposure of the rats to DMBA potentiates the hepatotoxic effects of DAB.Partial hepatectomy gives protection when performed 1 day before DMBA; shorter intervals give no protection. Some protection can be achieved with resection 6 or 24 hours after DMBA.NECROSIS of the adrenal cortex of the mature Sprague-Dawley rat induced by 7,12-dimethylbenz(a)anthracene (DMBA) can be prevented by treatment with carbon tetrachloride or by partial hepatectomy 24 hours before administration of the polycyclic compound (Wheatley, Kernohan and Currie, 1966b). This finding was the first indication that DMBA can only exert an adrenocorticolytic effect after it has been metabolized by the liver, Subsequent work has proved this to be the case and has shown that 7 -hydroxymethyl-12 -methylbenz (a) -anthracene is either an intermediate or a superior substrate from which the ultimate adrenal damaging agent arises (Boyland, Sims and Huggins, 1965;Wheatley et al., 1966a;Wheatley and Sims, 1969).The time intervals between treatments designed to impair liver function and the administration of DMBA are critical for achieving protection of the adrenal gland. In our original communication (Wheatley et al., 1966b) we confined our results to an interval of one day at which time the hepatotoxic action of CC14 was most pronounced and the effect of partial hepatectomy in altering liver function towards regeneration was maximal. The effects of varying the interval have proved to be very informative, however, and in this report the results with three methods of interfering with liver function -(i) CC14 treatment, (ii) p-dimethylaminoazobenzene (butter yellow, hereafter DAB), and (iii) partial hepatectomy (700o) are described. An interesting reciprocal relationship is shown between the protective action of pretreatments with hepatotoxins on adrenocorticolysis by DMBA, and effects of pretreatment with DMBA on the action of the hepatotoxins. It is also shown that normal liver functioning at the time of DMBA administration is indeed critical for the production of adrenocorticolysis and that the induction of liver damage with hepatotoxins after DMBA administration has little or no effect on the adrenocorticolytic phenomenon.

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“…Like many other agents, CCL is metabolized via cytochrome P-450 (25, 39) to yield a free radical (34,44,45,50,51), which may mediate subsequent damage. A number of subcellular processes/compartments are affected (including lipid peroxidation and Ca ++ influx), and a well-described morphologic sequence ensues (39, 46), although the basic mechanisms underlying the cellular injury are not clear (3, 40 53).…”

mentioning

confidence: 99%

Early hypomethylation of 2'-O-ribose moieties in hepatocyte cytoplasmic ribosomal RNA underlies the protein synthetic defect produced by CCl4.

Clawson¹,

MacDonald²,

Woo³

1987

The Journal of Cell Biology

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Abstract. Carbon tetrachloride (CCL) treatment of rats produces an early defect in methylation of hepatocyte ribosomal RNA, which occurs concurrently with a defect in the protein synthetic capacity of isolated ribosomes. The CCh-induced methylation defect is specific for the 2'-O-ribose position, and a corresponding proportional increase in mTG base methylation occurs in vivo. Undermethylated ribosomal subunits (rRNA) from CCl4-treated preparations can be methylated in vitro to a much greater extent than those from control preparations, and in vitro methylation restores their functional capacity. In vitro methylation of treated ribosomal subunits (which restores functional capacity) occurs at 2'-O-ribose positions (largely G residues). In contrast, in vitro methylation of control ribosomal subunits (which does not affect functional activity) represents base methylation as mTG, sites which are apparently methylated in treated preparations in vivo. Methylation/demethylation of 2'-O-ribose sites in rRNA exposed on the surface of cytoplasmic ribosomal subunits may represent an important cellular mechanism for controlling protein synthesis in quiescent hepatocytes, and it appears that CCL disrupts protein synthesis by inhibiting this 2'-O-ribose methylation.C ARBON tetrachloride (CCI4) ~ has long served as a model compound for study of hepatic injury (9,36,37,39,46). Like many other agents, CCL is metabolized via cytochrome P-450 (25, 39) to yield a free radical (34,44,45,50,51), which may mediate subsequent damage. A number of subcellular processes/compartments are affected (including lipid peroxidation and Ca ++ influx), and a well-described morphologic sequence ensues (39, 46), although the basic mechanisms underlying the cellular injury are not clear (3, 40 53).Early studies established the endoplasmic reticulum (ER) as the site of the first significant cellular changes (38,39,46). Altered ER structure occurs by 30 rain after oral CC14 administration (46, 47) and consists chiefly of a marked loss of ribosomes from rough ER ("degranulation') and a disaggregation of polysomes. Slightly later, other morphological changes in ER (such as tubular aggregates) can be detected.The major early functional defect involves protein synthesis (47); alterations in protein synthesis are specific for hepatocytes and parallel morphological alterations within the lobules (24). The nature of the protein synthetic defect is not

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Necrogenic Action of Carbon Tetrachloride in the Rat: A Speculative Mechanism Based on Activation

Cited by 436 publications

References 26 publications

STUDIES ON THE FUNCTION OF CELL MEMBRANE 10th REPORT :EFFECTS OF CCl4 ON THE MARKER ENZYME ACTIVITIES AND FINE STRUCTURES OF RAT LIVER PLASMA MEMBRANES AND MICROSOMES IN VITRO

STUDIES ON THE FUNCTION OF CELL MEMBRANE 10th REPORT :EFFECTS OF CCl4 ON THE MARKER ENZYME ACTIVITIES AND FINE STRUCTURES OF RAT LIVER PLASMA MEMBRANES AND MICROSOMES IN VITRO

Reciprocal Relationship Between the Production of Adrenal Damage by 7,12-Dimethylbenz(a)anthracene in Rats and the Induction of Liver Damage by Various Treatments

Early hypomethylation of 2'-O-ribose moieties in hepatocyte cytoplasmic ribosomal RNA underlies the protein synthetic defect produced by CCl4.

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