Dietrich Hoffmann

Binding of [G-3H]-7,12-dimethylbenz(α)anthracene to DNA of normal and of rapidly dividing hepatic cells of rats

Abstract The administration of tritium-labeled 7,12-dimethylbenz(α)anthracene (DMBA) to rats at 24 h after partial hepatectomy resulted in its binding to DNA in small intestine and regenerating liver. The binding in regenerating liver, which began 3 h after i.v. administration of DMBA, reached a maximum at 6 h and declined at 24 h; the uptake in intestinal DNA was similar but there was no decline for 48 h. The DMBA-induced inhibition of DNA synthesis paralleled uptake; both were dose dependent. More than twice as much DMBA was bound in vitro to DNA that had been isolated from livers of immature rats or from those undergoing regeneration than to DNA from livers of young adults. Such a difference was also observed in vivo. The possibility that the binding of DMBA is causally related to inhibition of DNA synthesis and carcinogenesis is discussed. Two forms of binding were apparent. In one the attractive forces were weak. In the other the binding resisted extensive dialysis, solvent extraction and denaturation. That the tightly bound form involved unchanged hydrocarbon was shown by direct gas-chromatographic analysis of the DNA-DMBA complex. The amount of DMBA tightly bound after i.v. injection of biologically active doses of 12.5–25 mg/kg corresponded to about 10·103–20·103 molecules per regenerating rat liver cell genome. This kind of interaction with DNA, which may be causally related to the mechanism of DMBA-induced oncogenesis, does not appear to require prior metabolic activation of the agent.

Some Laboratory and Epidemiological Aspects of Air Pollution Carcinogenesis

Chemical, analytical and biological studies were completed on the organic matter of large air pollution samples from Detroit. The high tumor response observed on mouse skin when the organic matter was applied in 12.5 per cent concentration can be partially explained by the presence of poly nuclear aromatic hydrocarbons (PAH) as tumor initiators and certain acidic components as tumor promotors. Certain polaric neutral components of still unknown nature are indicated also to act as tumor promotors. The concentrations of PAH in various locations in Detroit and New York during different seasonal, meteorologic and traffic conditions are compared. The relative importance of carcinogenic air pollutants in man’s environment is discussed in line with epidemiological evidence.

Beitrag zur carcinogenen Wirkung von Dibenzopyrenen

Nach Synthese und/order sorgfältiger Reinigung wurden neun hexacyclische Verbindungen im Pinselungstest im Vergleich zu Benzo(a)-pyren an der Maus auf ihre krebserzeugende und Tumor-Initiatowirkung geprüft. Es ergaben sich folgende Reihen der Aktivitäten: Als Vollcarcinogen sind Benzo(a) pyren (X) stark aktiv; dibenzo(a, h)pyren (IV), Dibenzo(a, l)pyren(I), und Dibenzo(a, i)pyren (V) aktiv; Dibenzo(a, e)pyren (II) und Indeno(1,2,3-cd)pyren (IX) schwach aktiv und Dibenzo(a, l)pyren (III), Dibenzo (cd-jk)pyren (VI), Benzo(ghi)perylen (VII) und Naphtho(2,3-e)pyren (VIII) inaktiv. Im Tumor-Initiatortest, in dem 2,5% Grotonöl als Promotor verwendet wurde, waren stark aktiv die Kohlenwasserstoffe X und IV; aktiv I und V; schwach aktiv II, VIII und IX; inaktiv die Verbindungen III, VI und VII. Die Ergebnisse der biologischen Versuche werden mit Berechnungen und Testen der Aktivitäten dieser polycyclischen Kohlenwasserstoffe verglichen. Da viele dieser Verbindungen in der Umwelt des Menschen vorkommen, sind die Beobachtungen von akademischer wie auch praktischer Bedeutung. Nine synthesized and/or highly purified hexacyclic aromatic hydrocarbons were tested for carcinogenicity and tumor-initiating potency on mouse skin. Their activities were compared with those of benzo(a)pyrene. The following order of activities was found: As complete carcinogen benzo(a)pyrene (X) rates strongly active; dibenzo(e, h)pyren (IV), dibenzo(a, l)pyrene (I) and dibenzo(a, i)pyrene (V) were active; dibenzo(a, e)pyrene (II) and indeno(1,2,3-cd)pyrene (IX) were weakly active and dibenzo(e, l)pyrene (III), dibenzo(cd-jk)pyrene (VI); benzo(ghi)perylene (VII) and naphtho(2,3-e)pyrene (VIII) were inactive. The initiator test for the polycyclic hydrocarbons made use of 2,5% Croton oil as promoter. The initiating activity was found to be strongly active for the polycyclic hydrocarbons X and IX; active for I and V, weakly active for II, VIII and IX and inactive for III, VI and VII. The results of the mouse skin tests are compared with data resulting from theoretical considerations and with predictions of carcinogenicity on the basis of physico-chemical reactions for these polynuclear aromatic hydrocarbons. Since many of these compounds occur in mans environment, these investigations are not only of academic but also of practical importance.Nach Synthese und/order sorgfaltiger Reinigung wurden neun hexacyclische Verbindungen im Pinselungstest im Vergleich zu Benzo(a)-pyren an der Maus auf ihre krebserzeugende und Tumor-Initiatowirkung gepruft. Es ergaben sich folgende Reihen der Aktivitaten: Als Vollcarcinogen sind Benzo(a) pyren (X) stark aktiv; dibenzo(a, h)pyren (IV), Dibenzo(a, l)pyren(I), und Dibenzo(a, i)pyren (V) aktiv; Dibenzo(a, e)pyren (II) und Indeno(1,2,3-cd)pyren (IX) schwach aktiv und Dibenzo(a, l)pyren (III), Dibenzo (cd-jk)pyren (VI), Benzo(ghi)perylen (VII) und Naphtho(2,3-e)pyren (VIII) inaktiv. Im Tumor-Initiatortest, in dem 2,5% Grotonol als Promotor verwendet wurde, waren stark aktiv die Kohlenwasserstoffe X und IV; aktiv I und V; schwach aktiv II, VIII und IX; inaktiv die Verbindungen III, VI und VII. Die Ergebnisse der biologischen Versuche werden mit Berechnungen und Testen der Aktivitaten dieser polycyclischen Kohlenwasserstoffe verglichen. Da viele dieser Verbindungen in der Umwelt des Menschen vorkommen, sind die Beobachtungen von akademischer wie auch praktischer Bedeutung.

A study of tobacco carcinogenesis. X. tumor promoting activity

Cigarette smoke condensate has been shown to have tumor‐promoting activity in the mouse skin bioassay system. The present study investigated the tumor‐promoting activity of tobacco extract and a variety of cigarette smoke condensates. On a gram‐to‐gram basis, the tumor promoting activity of a DMSO tobacco extract is similar to that of cigarette smoke condensate. In the setting of the present study, smoke condensate from cigarettes made wholly from tobacco stems showed no significant tumor‐promoting activity. Observations from this study should contribute towards the identification of the major tumor‐promoting agents in cigarette smoke condensate and tobacco extracts.

Tobacco carcinogenesis: IX. Effect of cigarette smoke on respiratory tract of mice after passive inhalation

Pathologic changes in the respiratory tract of “smoked” male C57BL mice were investigated. In a reduced pressure chamber animals were exposed to smoke of filter and nonfilter cigarettes, an admixture of volatile acids and aldehydes and NO2 One group of mice was inoculated with Swine influenza virus before smoke exposure. Histologic sections were taken from the nasal cavity and respiratory tree. Mice exposed to cigarette smoke and volatile agents appeared to have increased susceptibility to infections of the nasal cavity and respiratory tree. Incidence of hyperplasia and metaplasia increased in “smoked” mice and is considered secondary to inflammation. No progress of these changes occurred with prolonged exposure in either these mice or mice infected with Swine influenza virus. All changes were reversible.

Ciliatoxic components in cigarette smoke. III. In vitro comparison of different smoke components

The eulamellibranch gill technique shows by in vitro studies that cigarette smoke is a ciliastatic agent. This technique, which measures primarily the acute effect of volatile components in cigarette smoke, also shows that there is a different ciliatoxicity between filtered and nonfiltered cigarette smoke and that some cigarette filter media are more effective than others in reducing volatile components.

Chemical Composition and Tumorigenicity of Tobacco Smoke

Numerous biological studies have established the carcinogenicity of tobacco smoke. (1,2) Laboratory experiments identified three types of components which contribute to the overall carcinogenicity of the smoke. These are tumor initiators, tumor accelerators, and tumor promoters. (3)