A reactive metabolite of acetaminophen is hepatotoxic in humans when the drug is ingested in large overdoses. The ability of the human fetal and adult liver to oxidize acetaminophen by trapping the potentially toxic metabolite as a glutathione conjugate has been measured. Oxidation by fetal liver was approximately ten times slower than by adult liver. However, there was a definite increase in acetaminophen oxidation with fetal age. Isolated human fetal liver cells conjugated acetaminophen with sulfate but not with glucuronic acid. The results indicate that the human fetal liver is able to detoxify acetaminophen by conjugation. However, it also catalyzes the formation of an active metabolite of acetaminophen through oxidation. Hence the fetus remains at risk should a large dose of the drug cross into the fetal circulation.

In in vitro assays using methylated DNAs as substrates, human liver fractions were shown to be able to catalyze the removal of 06-methylguanine. The amount of removal was proportional to the amount of protein added, and the loss of O6-methylguanine occurred with stoichiometric formation of guanine in the DNA and S-methylcysteine in protein. This indicates that human liver contains a protein similar to that previously found in bacteria exposed to ailcylating agents. This protein acts as a transmethylase, transferring the intact methyl group from 06-methylguanine in DNA to a cysteine residue on that protein. A similar activity is present in rodent liver, butit was found that human liver was about 10 times more active in carrying out this reaction. In contrast, there was no difference between the human and rat liver extracts in catalyzing the loss of another methylation product, 7-methylguanine, from alkylated DNA. The liver is the organ most likely to be alkylated after exposure to exogenous potential alkylating agents such as dimethylnitrosamine. The present results show that human liver has a significant capacity to repair 06-methylguanine in DNA, which has been implicated as a critical product in carcinogenesis and mutagenesis. Dimethylnitrosamine (Me2NNO) is known to be carcinogenic in many animal species (1). This effect has been associated with the capacity of the target tissues to metabolize Me2NNO into a mutagenic intermediate that reacts with DNA at various sites (2-4). Of the various DNA adducts formed, 06-methylguanine (MeGua) has been implicated in both mutagenesis and carcinogenesis (4-10). The persistence of06-alkylguanine in the DNA of a tissue correlates with the probability that that tissue will develop tumors after administration of alkylating agents, indicating that this adduct is a critical determinant in the initiation of carcinogenesis by nitrosamines such as Me2NNO (4, 9, 10). MeGua can be removed from DNA in Escherichia coli by a DNA repair system which transfers the methyl groups to a cysteine residue in protein (11,12). There is evidence that this system also occurs in rodent tissues, but it has not been fully characterized (4,(13)(14)(15)(16)(17). Humans are known to be exposed to nitrosamines, including Me2NNO (18,19), and Me2NNO is metabolized by human liver to generate the reactive intermediate that results in DNA alkylation (20,21).In the work presented here, we used an in vitro assay to demonstrate that human liver fractions can catalyze the removal of MeGua from DNA; we found that this capacity is about 10 times greater than that with comparable rat liver fractions. We have also shown that this human liver system transfers the methyl group from the 06 position of guanine to eysteine residue, regenerating guanine directly in the DNA. MATERIALS AND METHODS Chemicals. N-[3H]Methyl-N-nitrosourea (1.6 Ci/mmol; I Ci = 3.7 X 1010 becquerels) was obtained from New England Nuclear. All other biochemical reagents were obtained from Sigma.Tissues. The 10 samples of human liver (six m...

Remoxipride is a new antipsychotic drug that binds selectively to the D2‐dopamine receptor subtype as demonstrated in animal studies in vitro and in vivo. It is generally assumed that the antipsychotic effect of neuroleptic drugs is mediated by blockade of dopamine receptors. The aim of the present study was to use positron emission tomography (PET) and the ligand [C] raclopride to examine the central D2‐dopamine receptor occupancy in man during oral administration of remoxipride. After oral administration of remoxipride 100 mg three times daily to a healthy male subject there was a 73% central D2‐dopamine receptor occupancy. In a schizophrenic patient treated with remoxipride 200 mg twice daily there was a 71 % occupancy. These occupancy values are similar to the values of 65–85% previously found in a series of patients treated with neuroleptics representative of all currently used chemical classes. In a separate experiment, remoxipride was labelled with C and injected intravenously and the distribution of radioactivity to the brain examined. Radioactivity appeared in the brain during the first minutes after injection and 4.5 min after injection it accounted for 0.8% of the total radioactivity injected, thus indicating that [C]remoxipride had rapidly passed through the blood‐brain barrier.

Six female and six male healthy volunteers received 100 mg remoxipride, 200 mg sulpiride and placebo as single oral doses in a double blind trial with a randomized crossover design. The main objective was to compare the effect of the two drugs on serum prolactin levels, but effects on other hormones were also investigated. Remoxipride and sulpiride increased the serum levels of prolactin to similar peak levels. This effect was larger in female than in male subjects. Sulpiride increased prolactin levels at much lower plasma concentrations than remoxipride, and sulpiride's effect on prolactin lasted for considerably longer than remoxipride's. No consistent effects on serum levels of LH, FSH, GH, oestradiol, progesterone, testosterone or cortisol could be detected after remoxipride and sulpiride compared to placebo. No drug-related effects on plasma homovanillic acid (HVA) were found.

1 The prolactin response following administration of the D2-dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3 TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.