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

Abstract

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.