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Dimethylnitrosamine (N-nitrosodimethylamine) has been shown to cause acute centrilobular necrosis of the liver in several mammalian species, including the rat (Barnes & Magee, 1954). It is carcinogenic in the rat, producing tumours of the liver (Magee & Barnes, 1956; Schmahl & Preussmann, 1959) and of the kidney (Magee & Barnes, 1959; Zak & Holzner, 1959). The compound is rapidly metabolized in vivo (Magee, 1956; Dutton & Heath, 1956; Heath & Dutton, 1958) and in vitro by liver slices and broken-cell preparations (Magee & Vandekar, 1958). When given to rats in doses sufficient to cause necrosis of the liver (50 mg./kg. body wt.) incorporation of isotopicaily labelled amino acids into liver proteins was greatly reduced 3 hr. after the administration of the poison, but no effect was observed in other organs. At this time, histological evidence of damage to the liver was minimal or absent. A smaller

The effect of administration of carbon tetrachloride and dimethylnitrosamine in vivo on hepatic microsomal function related to drug metabolism was measured. It was found that the capacity of isolated microsomes to demethylate dimethylaniline was diminished during the first hour after carbon tetrachloride poisoning and during the second hour after dimethylnitrosamine poisoning. Thereafter the microsomes from carbon tetrachloride-poisoned livers showed a continuous decline in activity so that at 24hr. there was little residual capacity to undertake demethylation. Microsomes from dimethylnitrosamine-poisoned animals were not different from controls at 24hr. During the first 3hr. there was a transient rise in the accumulation of the N-oxide intermediate in carbon tetrachloride-poisoned livers, with a subsequent fall to below control values. In dimethylnitrosamine poisoning there was a parallel decrease in N-oxide accumulation with decreased demethylation. In the latter part of the first 24hr. the ratio of N-oxide accumulation to demethylation was increased in both instances. At 2hr. after poisoning with either compound there was no evidence of altered NADPH(2)-dependent neotetrazolium reduction or lipid peroxidation. NADPH(2)-dependent azo-dye cleavage was decreased. There was no difference in microsomal cytochrome b(5) content, but there was a decrease in the amount of cytochrome P-450. This latter change was correlated with the decreased capacity for NADPH(2)-dependent oxidative demethylation. It is suggested that dimethylnitrosamine is associated with a defect in microsomal NADPH(2)-dependent electron transport at the level of cytochrome P-450. In addition to affecting cytochrome P-450, carbon tetrachloride is associated with a second severe block involving the release of formaldehyde from the N-oxide intermediate.

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