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. 2017 Sep 1;7(4):167–173.

Hepatic metabolism of 11C-methionine and secretion of 11C-protein measured by PET in pigs

Jacob Horsager 1, Susanne Bach Lausten 2, Dirk Bender 1, Ole Lajord Munk 1, Susanne Keiding 1,3
PMCID: PMC5596319  PMID: 28913155

Abstract

Hepatic amino acid metabolism and protein secretion are essential liver functions that may be altered during metabolic stress, e.g. after surgery. We wished to develop a dynamic liver PET method using the radiolabeled amino acid 11C-methionine to examine this question. Eleven 40-kg pigs were allocated to either laparotomy or pneumoperitoneum. 24 hours after surgery a 70-min dynamic PET scanning of the liver with arterial blood sampling was performed immediately after intravenous injection of 11C-methionine. Time course of arterial plasma 11C-methionine concentration was used as input function and that of liver tissue 11C-concentration as output function in an extended Patlak analysis that accounted for irreversible metabolism of 11C-methionine (hepatic systemic metabolic clearance K met) and secretion of 11C-protein + 11C-metabolites into blood (rate constant k loss). Appearance of 11C-proteins in arterial plasma was measured during the experiment. There were no statistically significant differences between the laparotomy group and the pneumoperitoneum group in any of the calculated parameters. Average mean hepatic systemic metabolic clearance K met was 0.212 mL plasma/mL liver tissue/min, secretion rate constant from liver to blood k loss 0.0054 min-1, flux of methionine F flux 3.59 μmol methionine/mL liver tissue/min, and the appearance rate of 11C-proteins in plasma R prot 0.048 kBq/mL plasma/min. There was significant correlation between K met and R prot. In conclusion, the hepatic systemic metabolic clearance of 11C-methionine was significantly correlated to the appearance rate of 11C-proteins in plasma. It would be interesting to translate the present method to human studies for the development of a clinical quantitative test of hepatic protein secretion.

Keywords: Methionine, liver metabolism, amino acids, hepatic protein secretion

Introduction

Metabolism of amino acids is a vital liver function involving synthesis and secretion of proteins to blood, e.g. albumin and immunoglobulins, but also gluconeogenesis and secretion of acute phase reactants during metabolic stress [1]. Methionine, an essential amino acid, is utilized in the liver for protein synthesis, transmethylation reactions e.g. for phospholipid synthesis, and as precursor for cysteine and taurine [2,3]. The radiolabeled methionine analog L-[methyl-11C]-methionine (11C-methionine) has been proposed as a tracer for measurement of hepatic protein synthesis in rats and mice, but this is a difficult task because 11C-methionine also undergoes transmethylation for phospholipid synthesis [4-9]. However, the liver is the main contributor to labeled plasma proteins after injection of 11C-methionine in humans [10]. Using positron emission tomography (PET) the metabolism of 11C-methionine was used to measure pancreatic exocrine function in humans [11], salivary gland function after radiotherapy in humans [12], and protein synthesis in muscle tissue in dogs and humans [13,14].

During metabolic stress, e.g. after surgery, amino acids are released from muscle tissue by protein breakdown and used for catabolic processes in the liver [1]. Laparoscopic surgery provides less postoperative catabolic stress response than laparotomy [15-19]. In the present study we investigated the hepatic metabolism of 11C-methionine by PET and hepatic secretion of 11C-proteins into plasma in pigs subjected to laparotomy compared to pigs subjected to minimal invasive technique by pneumoperitoneum.

Material and methods

Radiotracer production

11C-methionine was produced applying an adopted standard procedure using S-[11C]methylation of homocysteine thiolactone with [11C]methyl iodide in acetone in the presence of 0.3 M sodium hydroxide solution, followed by preparative HPLC [20]. For preparative HPLC a 250 x 10 mm Phenomenex Sphericlone ODS with saline as eluent and a flow rate of 4 mL/min was used. The molar activity, formerly known as specific radioactivity, exceeded 20 GBq/µmol at time of injection for all examinations (tracer release criteria for 11C-methionine).

Animal preparation

Twelve female pigs of Danish landrace weighing 39-42 kg (mean; 41 kg) were included but one pig died during surgery due to hyperthermia and was excluded. The animals were housed and cared for at the animal farm of Aarhus University in accordance with requirements for animal care stipulated by the Danish Animal Experimentations Inspectorate under the Ministry of Justice. Animals were allocated into two groups, laparotomy (n = 6) and pneumoperitoneum (n = 5). Before surgery the animals fasted for 16 hours with free access to water. Anesthesia was initiated by intramuscular injection of ketamine (Ketalar), 10 mg/kg BW and midazolam, 0.5 mg/kg BW, followed by intubation and volume controlled ventilation. Pneumoperitoneum was established by insertion of a Veress cannula through a 10-mm sub-umbilical skin incision and insertion of four trocars, two of 5 mm and two of 10 mm, in the position for laparoscopic cholecystectomy (SurgiPort; United States Surgical Coorporation, Norwalk, CT, USA). Pneumoperitoneum was maintained continuously for 90 minutes. Laparotomy was performed by a 15 cm long transverse subcostal incision, mimicking the incision used for an open cholecystectomy. The abdominal wall was opened with electrocautery and a retractor was placed in the wound for 90 minutes and then sutured in two layers. The animals were housed at the animal farm of Aarhus University to the next morning. After completion of the experimental PET procedures described below, euthanasia was performed by an intravenous injection of phenobarbital in a dose of 100 mg/kg. The liver was removed and weighted (mean; 883 g, range; 740-1025 g).

PET examination

24 hours after surgery the animals were anaesthetized, intubated and ventilated for the PET procedure. A catheter was inserted into the femoral vein for injection of 11C-methionine, and another in the femoral artery for arterial blood sampling. The animals were placed in supine position with the liver in the 15-cm field of view of the PET-camera (Siemens ECAT EXACT HR-47 tomograph, CTI/Siemens Medical Systems, Knoxville, USA).

After a 15-minutes transmission scan for attenuation correction, 500 MBq L-[methyl-11C]-methionine, produced in the radiochemistry facility at the PET Centre [20], was injected intravenously over 12 seconds in the beginning of a 70-min dynamic scanning of the liver with time frame structure 12 x 5 s, 3 x 10 s, 3 x 30 s, 7 x 60 s, and 6 x 600 s. Data was reconstructed with filtered back projection using a Hann filter with a cut-off frequency of 0.2, 128 x 128 x 47 matrix and voxel size 2.0 x 2.0 x 3.1 mm3. Data was recorded as integrated mean values in each of the time frames and corrected for radioactive decay back to start of the scan.

Liver regions of interests (ROIs) were drawn in adjacent slices on the PET image in the last time frame, with a minimum of one cm from the edge in the right liver lobe. ROIs were summed to form a volume of interest (Liver-VOI: mean; 26.2 mL, range; 15.8-34.2 mL) (Figure 1).

Figure 1.

Figure 1

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Transaxial slice of the PET image of the liver in the last time frame (Pig 9). Liver-ROI shown in black. Similar adjacent ROIs were summed to form a Liver-VOI.

Blood analysis

Arterial blood samples (1 mL) were taken during the scans at 12 x 5 s, 2 x 10 s, 1 x 20 s, 2 x 30 s, 1 x 45 s, 6 x 60 s, 1 x 330, and 5 x 600 s, a total of 65 minutes (last sample corresponding to mid-point of last time-frame of the PET scan) and plasma 11C-concentrations were measured using a well counter (Cobra II, Packard Instruments Co., Meriden, CT). Fractions of un-metabolized 11C-methionine and of 11C-metabolites in plasma were measured in 2 mL blood samples taken 0, 2, 5, 10, 15, 35, and 55 min after tracer injection. 11C-protein was precipitated by addition of 500 µL 10% sulfosalicylic acid to 500 µL plasma, taken at 2, 5, 10, 15, 25, 35, 45, 55 and 65 min after tracer injection and after centrifugation the precipitate 11C-concentration was measured in the well counter. Precipitate radioactivity was corrected for trapped supernatant radioactivity. The supernatant was analyzed for 11C-metabolites by radio-HPLC on a Pnenomenex Sphereclone ODS(2) column (pore size 5 µm) measuring 250 x 4.6 mm (Phenomenex, Torrance, CA, US). The eluent was a mixture of 0.1 M sodium dihydrogen phosphate, 2.6 mM octanesulphonic acid sodium salt and 0.1 mM EDTA, pH adjusted to 3.3 with acetic acid. The flow rate was 2 mL/min, and radioactivity was continuously measured using a NaI scintillation detector (Gabi, Raytest, Germany) in series to the UV detector. All plasma 11C-concentration measurements were corrected for radioactive decay back to start of the scan.

Plasma 11C-radioactivity concentrations were corrected for average time course of the fractions of 11C-proteins and 11C-metabolites using a fitted monoexponential function (Figure 2). Figure 3 shows an example of the time courses of 11C-radioactivity concentration in liver tissue VOI and plasma concentration of un-metabolized 11C-methionine.

Figure 2.

Figure 2

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Average time course of the fraction of 11C-methionine concentration in arterial plasma (“free fraction”) (y-axis) versus time after injection of 11C-methionine (x-axis; minutes) with all individual data shown along with the fitted monoexponential equation.

Figure 3.

Figure 3

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Time courses of 11C-radioactivity concentration in liver tissue (black, dashed), 11C-methionine concentration in arterial plasma (red, solid), and 11C-protein concentration in arterial plasma (blue, dotted). Pig no. 9.

Plasma concentration of unlabeled methionine was determined after precipitation of plasma proteins (see above) by analytical HPLC applying a Phenomenex Sperisorb NH2 column, 250 x 4.6 mm. acetonitrile:water 70:30 as eluent, flow rate 1 mL/min and 230 nm detection wavelength. The concentration of methionine was calculated by comparison of the area under the methionine peak to the area obtained from a reference solution of methionine with known concentration.

Data analysis

Data was analyzed by an extended Patlak analysis [21] that accounts for irreversible metabolism of 11C-methionine (hepatic systemic metabolic clearance, K met) and loss of metabolized 11C-tracer to blood (rate constant, k loss). The time course of arterial concentration of 11C-methionine was used as input function and the time course of 11C-concentration in liver tissue 15-70 min after tracer injection as output function. For this analysis, a single arterial input can replace dual input from the portal vein and hepatic artery [22]. The compartmental model of the hepatic 11C-methionine metabolism (Figure 4), was used to calculate; i) the hepatic systemic metabolic clearance of 11C-methionine, K met (mL plasma/mL liver tissue/min) as a measure of intracellular conversion of 11C-methionine to 11C-protein and 11C-metabolites, and ii) the secretion rate constant, k loss (min-1), interpreted as the fraction 11C-concentration in the Liver-VOI secreted to blood as 11C-proteins + 11C-metabolites per minute. The appearance rate of 11C-proteins in plasma, R prot (kBq/mL plasma/min), was determined as the slope of the linear regression of the time course of plasma 11C-protein concentration (Figure 3). The flux of unlabeled methionine from plasma into liver tissue, F flux (μmol methionine/mL liver tissue/min) was calculated as K met multiplied by plasma methionine concentration (μmol methionine/mL plasma).

Figure 4.

Figure 4

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Compartment model of hepatic 11C-methionine metabolism. K met, the hepatic systemic metabolic clearance of 11C-methionine (mL plasma/mL liver tissue/min), k loss, the secretion rate constant of 11C-protein + 11C-metabolites from hepatocytes to blood (min-1).

Statistics

Differences among the groups of animals were analyzed using unpaired t-test. Pearson product moment correlation coefficient was used to evaluate the correlation between the estimated parameters. A P-value of ≤ 0.05 was considered to indicate statistical significance.

Results

The time courses of the radioactivity concentrations in arterial plasma and liver tissue are illustrated in Figure 3. The plasma concentration of 11C-methionine showed an initial peak and then decreased to a low level and kept decreasing throughout the experimental period. The 11C-concentration in liver tissue increased rapidly to near steady-state and, after a delay of approx. 17 min, 11C-protein plasma concentration increased linearly.

The extended Patlak model fitted the measurements well with no systematic or significant deviations. There were no statistical significant differences of any of the metabolic parameters between the laparotomy and pneumoperitoneum groups (Table 1; every P > 0.6). The concentration of unlabeled methionine was also not statistically significantly different between the two groups (average mean; 18.1 μmol methionine/mL plasma, range; 6.6-24.5 μmol methionine/mL plasma, P = 0.41). We therefore combined data from the two groups in the further analysis.

Table 1.

Hepatic metabolism of 11C-methionine in pigs

K met (mL plasma/mL liver tissue/min) k loss (min-1) F flux (µmol methionine/mL liver tissue/min) R prot (kBq/mL plasma/min)
Procedure Lap Pneu Lap Pneu Lap Pneu Lap Pneu
Pig 1 and 2 0.231 0.216 0.0037 0.0056 4.34 1.43 0.085 0.049
Pig 3 and 4 0.122 0.411 0.0028 0.0119 1.80 7.72 0.037 0.083
Pig 5 and 6 0.290 0.175 0.0070 0.0068 5.53 2.98 0.061 0.008
Pig 7 and 8 0.338 0.124 0.0090 0.0043 n.d. 2.02 0.055 0.038
Pig 9 and 10 0.086 0.179 0.0033 0.0011 1.81 4.41 0.021 0.045
Pig 11 0.163 0.0038 3.89 0.051
Mean 0.205 0.222 0.0049 0.0059 3.47 3.71 0.052 0.045
P 0.81 0.62 0.86 0.64
Average mean (n = 11) 0.212 0.0054 3.59 0.048
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Lap, laparotomy; Pneu, pneumoperitoneum; K met, hepatic metabolic clearance of 11C-methionine; k loss, rate constant of secretion of 11C-protein and 11C-metabolites from liver tissue to blood; F flux, flux of methionine from plasma to liver tissue; R prot, rate of appearance of 11C-protein in plasma; n.d., not determined.

K met was significantly correlated with R prot (P = 0.015) (Figure 5), i.e. the hepatic systemic metabolic clearance of 11C-methionine from plasma (measured by PET), was significantly correlated to the appearance rate of 11C-proteins in plasma (measured from blood sampling).

Figure 5.

Figure 5

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Scatter plot of relation between R prot, appearance rate of 11C-protein in plasma, and K met, hepatic systemic metabolic clearance of 11C-methionine in 11 pigs. Linear regression line is shown. The correlation coefficient, r, is 0.71 (P = 0.015).

The intercept on the abscissa of the linear regression of the time course of the plasma concentration of 11C-protein was on average 16.7 minutes (range, 9.6-36.2 minutes), reflecting the time delay from tracer injection to appearance of 11C-proteins in plasma, secreted by the liver.

Discussion

The main result of the present study is that the PET-measured hepatic systemic metabolic clearance of 11C-methionine (K met) correlated significantly to the blood-measured appearance rate of 11C-protein in blood (R prot). This suggests that dynamic PET of the liver with 11C-methionine can be used to measure hepatic protein secretion because the liver is the main contributor of plasma proteins. Clinically, plasma albumin concentration is routinely used as a surrogate measure of hepatic protein synthesis but the albumin concentration can be reduced not only in patients with liver disease but also in patients without liver impairment, for example patients with kidney disease. The use of plasma albumin may thus be replaced by dynamic 11C-methionine PET of the liver in clinical situations where a specific measure of the hepatic protein production and secretion is wanted, for example in patients with ascites or after liver transplantation. This is an interesting aspect because other liver tests measure uptake from blood and metabolism [23,24] or hepatobiliary excretion [25,26].

The hepatic catabolic stress response, measured by functional hepatic nitrogen clearance, was found significantly higher in pigs exposed to laparotomy compared to pneumoperitoneum [18] which was not confirmed in the present study. We would expect that the laparotomy pigs would have a higher amino acid turn over and thus a higher K met and F flux compared to the pneumoperitoneum pigs. However, an indispensable amino acid, as methionine, might not follow the pattern of higher hepatic metabolism rate during catabolic stress, because the degradation from protein might be down regulated and the body try to preserve methionine instead of elimination trough e.g. transsulfation [3]. This could explain why no significant difference in K met or F flux was found in the present study between pneumoperitoneum and laparotomy. 11C-methionine might thus not be the best tracer to quantify hepatic stress response.

In humans the most abundant metabolites from methionine are 4-methylthio-2-oxobutyrate (deaminated methionine) and serine [10]. We did not perform separate analyses of the amino acids but the input function was corrected for 11C-metabolites. However, any possible uptake of 11C-metabolites by the hepatocytes would imitate 11C-methionine and influence the time course of 11C-concentration in liver tissue (PET) which would result in overestimation of K met. However, if we calculated K met 5-15 min after injection, where only minor amounts of metabolites were present, mean K met 0.237 mL plasma/mL liver tissue/min was not significantly different to the present mean K met 0.212 mL plasma/mL liver tissue/min (paired t-test, P = 0.10). The error from this possible bias is acceptable. In this context, it should be emphasized that if a simple Patlak model without k loss was applied to the data, the difference become significant (paired t-test, P < 0.001, data not shown) reflecting the importance of k loss in the analysis.

In order to measure plasma 11C-protein for estimation of R prot, we precipitated plasma with sulfosalicylic acid, but a study in mice showed that 19% of metabolites in plasma, 60 minutes after injection of 11C-methionine was actually lipids and derived from the acid precipitable fraction [7]. However, 36% was protein and 45% was other (non-acid precipitable) metabolites. Furthermore, in a human study, incorporation of [methyl-2H3]-methionine into proteins were almost 4 times faster than transmethylation (e.g. for lipid synthesis) in the post absorptive state [3]. The pigs in our study had fasted for 16 hours before the PET examination, so the main radioactivity in the precipitate is thus most likely from 11C-proteins. The 11C-proteins appeared in plasma on average 16.7 min after tracer injection which was comparable to a study in humans [10] and probably due to synthesis and transport of 11C-proteins in the hepatocytes.

In conclusion, we developed a functional PET method for quantification of hepatic 11C-methionine metabolism in pigs and found a significant correlation to the appearance rate of 11C-proteins in plasma. We found no significant difference in metabolism of 11C-methionine between the laparotomy group and the pneumoperitoneum group. Dynamic 11C-methionine PET of the liver may prove clinically useful as a quantitative liver test of the hepatic protein secretion but this need to be confirmed in a human study.

Disclosure of conflict of interest

None.

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